US010378059B2 (12 ) United States Patent (10 ) Patent No. : US 10 , 378 , 059 B2 Karmali (45 ) Date of Patent: Aug. 13 , 2019 (54 ) METHODS AND MOLECULAR OTHER PUBLICATIONS PHARMACODYNAMIC BIOMARKERS FOR Loboda et al. ( A gene expression signature of RAS pathway MULTIPLE SIGNALING PATHWAYS IN dependence predicts response to P13 and RAS pathway inhibitors RESPONSE TO CARBOXYAMIDOTRIAZOLE and expands the population of RAS pathway activated tumors , OROTATE BMC Medical Genomics, Jun . 30 , 2010 , 3 :26 , pp . 2 - 11 ). * Loboda A et al. (Biomarker Discovery : Identification of a Growth ( 71 ) Applicant: Rashida A Karmali , New York , NY Factor Gene Signature. Clin Pharmacol Ther. 2009 , 86 : pp . 92 - 96 ) . * U . Guhnthert et al . ( Book : Attempts to Understand Metastasis (US ) Formation II ), Springer , 1996 , 11 pages. * Roderick et al. ( “ Ca2 + signaling checkpoints in cancer : remodeling (72 ) Inventor: Rashida A Karmali, Brooklyn , NY Ca2 + for cancer cell proliferation and survival, ” Nature Reviews Cancer, 2008 , 8 , pp. 361 - 375 ( Year: 2008 ). * ( US ) NCI drug dictionary . * Young K et al, Exp Cell Res 314 :2750 - 2761 ( 2008 ) . Witt O et al, Cancer Letter 277 : 8 -21 ( 20080 . (73 ) Assignee : TACTICAL THERAPEUTICS, INC ., Wang et al Mol Cancer Ther 12 : 925 - 936 ( 2013 ) . New York , NY (US ) Tan J et al , Mol Cancer Ther 12 : 853 - 864 ( 2013 ) . Stambolic V et al, Mol Cell 8 :317 - 325 ( 2001 ) . Subject to any disclaimer , the term of this Smith A et al Clin Cancer Res 18 : 4514 -4512 (2012 ). ( * ) Notice : Nusse R Cell Res 15 ; 28 - 32 ( 2005 ) . patent is extended or adjusted under 35 Mignen O et al J Cell Sc 118 :5615 - 5623( 2005 ) . U . S . C . 154 (b ) by 1056 days . Loboda A et al Clin Pharm & Ther 86 : 92 - 96 (2009 ) Loboda A et al BMC Medical Genomics 3 : 1 - 11 ( 2010 ) . Liu C et al Proc Natl Adcad Sc 93 : 11831 - 36 ( 1996 ) . (21 ) Appl. No. : 13 /957 , 720 Lawson EL et al PLOS ONE 7 : 1 - 14 ( 2012 ) . Kohn EC et al Cancer Res 52 : 3208 - 3212 ( 1992) . Kohn EC et al Proc natl Adac Sc 92 : 1307 - 1311 ( 1995 ) . ( 22 ) Filed : Aug. 2 , 2013 Hupe DJ et al JBiol Chem 266 : 10136 -42 ( 1991 ) . Gou HF et al PLOS ONE 8 : 1 - 6 ( 20130 . Ge S et al Clin Cancer Res 6 : 1248 - 1254 ( 2000 ) . (65 ) Prior Publication Data Garon EB et al Mol Cencer Ther 12 : 890 - 900( 2013 ) . US 2015 / 0038349 A1 Feb . 5 , 2015 Enfissi E et at Cell Calcium 36 : 450 - 467 ( 2004 ) I . Felder CF et al J Pharm Exp Ther 257 : 967 -971 ( 1990 ) . De Robertis A et al, Mol Cancer Ther 12 : 1180 - 1189 ( 2013 ) . (51 ) Int. Ci. Collin I et al , Cancer Signal Trans Ther 1 : 3 -23 ( 2006 ) . Song S et al , PLOS 7: 1 - 11( 2012 . GOIN 33 / 50 ( 2006 .01 ) Janku F et al, J Clin Onc 30 : 777 - 782 ( 2012 ) . C120 1/ 6886 (2018 . 01 ) Fiorio et al Mol Canc Res 6i 535 -545 ( 2008 ). G16B 20 /00 ( 2019 . 01 ) Alesandro et al J . Cell . Physiol 215 : 111 ( 2008 ) . (52 ) U . S . CI. CPC .. . C12Q 1/ 6886 ( 2013 .01 ); C12Q 2600 /106 * cited by examiner (2013 .01 ); C12Q 2600 /158 (2013 .01 ) ; G16B Primary Examiner — Jason M Sims 20 / 00 ( 2019 .02 ) (74 ) Attorney, Agent, or Firm — Rashida A . Karmali , (58 ) Field of Classification Search Esq . None (57 ) ABSTRACT See application file for complete search history . This invention provides methods , pharmacodynamics bio marker signatures for multiple signaling pathways in a cell sample such as anagen hair , in response to carboxyamido ( 56 ) References Cited triazole orotate (CTO ) from a subject. CTO has demon strated response in several cancers having different genomic U . S . PATENT DOCUMENTS mutations in clinical studies . This invention provides a 8 , 357 ,514 B2 1 / 2013 Arunakumari diagnostic and prognostic assay for monitoring response to 8 ,409 , 796 B2 4 / 2013 Cullen CTO ranging from - 100 fold to + 25 fold differential expres 8 , 450 , 057 B2 5 / 2013 Gordon sion in several transcriptional signatures associated with 2003/ 0170720 A1 * 9 / 2003 Van der Kuyl ...... C12Q 1 /6886 tumor inhibition including EGFR , MEK , HDAC , RAS , 435 / 7 . 1 GFS , WNT, HSP90 or non -voltage dependent calcium sig . 2008/ 0139592 A1 * 6 / 2008 Karmali ...... A61K 31/ 4192 naling, while inducing tumor suppressors signatures such as 2012/ 0202760 A1 * 8/ 2012 Karmali...... CO7D514 249 / 274 /04 P53 or EGR1 in the anagen hair assay. 514 / 34 28 Claims, 8 Drawing Sheets atent Aug . 13, 2019 Sheet 1 of 8 US 10, 378 ,059 B2

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METHODS AND MOLECULAR control many oncogenic players and pathways in malig PHARMACODYNAMIC BIOMARKERS FOR nancy , for example inhibitors of histone deacetylases MULTIPLE SIGNALING PATHWAYS IN (HDAC ) and the HSP90 molecular chaperone. Garon E . B , RESPONSE TO CARBOXYAMIDOTRIAZOLE et al, Mol Cancer Ther. , 12 : 890 - 900 ( 2013 ) ; and Witt O at OROTATE 5 al, Cancer Letters 277 : 8 - 21 (2009 ). Screening and structure -based design of targeted drugs FIELD OF INVENTION against oncogenic markers driving specific cancers are now delivering targeted drugs for preclinical and clinical studies This invention is related to evaluation ofmolecular phar- at a rapid rate . However, there is need to study signaling macodynamics markers in response to carboxyamidotriazole 10 pathways in normal cells to better understand the factors that orotate (CTO ) in ex vivo human anagen hairs obtained from cause important tumor suppressor proteins to fail as gate healthy subjects or patients with different diseases . CTO is keepers of normal cellular function . There is need to better an orally active agent with antineoplastic activity, that understand how these tumor suppressor proteins may be inhibits non - voltage operated Ca2 + channels , blocking both modulated to prevent loss of their normal signaling in Ca2 + influx into cells and Ca2 + release from intracellular 15 response to stress signals . stores and resulting in the disruption of calcium -mediated More particularly , it is important to develop drugs that can signal transduction and inhibition of vascular endothelial aid normal cells to integrate multiple signaling pathways or growth factor (VEGF ) signaling , multiple tyrosine kinase enhance their role as gate keepers to control growth and signaling , including AKT, MEK - ERK , or Ber- Abl. More proliferation . For example , the P53 transcription factor is a particularly , the present invention relates to the evaluation of 20 major tumor suppressor protein that serves as a gatekeeper molecular pharmacodynamics biomarkers of overall signal- of cellular fate in multicellular organisms. P53 is activated ing output by transcriptomic assessment of response to CTO in response to a variety of stress signals and initiates cell given to patients or when added to ex vivo cultured human cycle arrest, senescence or apoptosis via pathways involving anagen hairs in vitro . transactivation of P53 target genes . Stambolic V et al . , Mol 25 Cell: 317 - 325 ( 2001 ) . This universal protection of genetic 1 . BACKGROUND TO THE INVENTION integrity is however impaired in many human cancers . The new paradigm is to develop agents that target the precise The development of new cancer drugs is now based on the molecular signaling that maintains normal cell cycle , growth identification of genes that are responsible for driving malig - and proliferation . nancy and the elucidation of the signal transduction path - 30 Thus, the rational selection and development of combi ways that they hijack . Tremendous advances have been nation treatments is extremely challenging and there is need made in the area of small molecule kinase inhibitors to to develop combinations of targeted drugs and or chemo develop targeted therapies designed to interfere with critical therapeutic agents based on knowledge of the molecular molecules and signaling pathways driving tumor growth , for abnormalities in particular cancers, together with the under example , Imatinib® ( BCR -ABL ) , Gefitnib® ( EGFR ) , Erlo - 35 standing of the feedback loops that apply upon blockade of tinib® , ( EGFR ) and many other agents under preclinical and a given pathway, as well as enhancing the tumor suppressor clinical development. It is important to focus on the phar - signaling pathways of p53 transcription factor and PTEN in macokinetic and metabolic properties as well as on target normal and cancer cells . potency and molecular selectivity to optimize the effects of Carboxyamidotriazole orotate (CTO ) , an orotate salt of targeted therapies. Collin , I and Workman , Cancer Signal 40 carboxyamidotriazole (CAI ) is an inhibitor of receptor Transduction Therapy, 1 : 3 - 23 (2006 ) . In the clinical devel- operated calcium channel- mediated calcium influx , and is opment of the kinase inhibitors, it is important to develop shown to have anti - proliferative and anti - invasive functions robust and informative biomarkers and develop assays for in several human cancer cell lines, including human glio predicting molecular dependence and hence for identifying blastoma cells . Ge S et al. Clin Cancer Res 6 : 1248 - 1254 patients who will benefit from personalized medicine from 45 ( 2000 ) . By interrupting calcium mobilization as a second a particular agent, and the problem of drug resistance messenger , CAI can inhibit calcium -sensitive signal trans developing duction pathways, including the release of arachidonic acid Another challenge facing the development of molecular and its metabolites ; nitric oxide release: the generation of therapeutics is the likely need to inhibit several oncogenic inositol phosphates ; and tyrosine phosphorylation Kohn EC targets in order to overcome cancers that are driven by 50 et al. , Cancer Res 52 : 3208 - 3212 ( 1992 ) ; Kohn E C et al. , several abnormalities, as well as to prevent or neutralize the Proc Natl Acad Sci 92 : 1307 - 1311 (1995 ) ; Felder C F et al. development of drug resistance . In some cases resistance to J Pharmacol Exp Therap 257 : 967 - 971 (1990 ); Hupe D J et a drug may be linked to increased production of molecules al. , J Biol Chem 266 : 10136 - 10142 ( 1991 ) ; Mignen O et al. , ( e .g . , cytokines, calcium channel signaling , or molecular J Cell Sc 118 : 5615 -5623 (2005 ) ; and Enfissi E et al. , Cell signaling ) in the tumor micro - environment that interferes 55 Calcium 36 : 459 -467 (2004 ) . CAI inhibits phosphorylation with the sensitivity and efficacy of the drugs. Therefore , of cellular proteins STATS and CrkL , and induces apoptosis even the most rationally conceived drug molecule may fail in imatinib mesylate -resistant chronic myeloid leukemia because of mutational changes downstream from its cells by down -regulating BCR - ABL ( Alessandro et al, intended target or metabolic features of tumors that never PLOS 7 : 1 - 13 ( 2012 ) . allow the drug to reach its target or that trigger feedback 60 In clinical studies (NCT01107522 ) CTO given alone was mechanism against the drug molecule . safe and tolerable without determining maximum tolerated There are several methods currently in use to overcome dose , in cancer patients with different tumor types and drug resistance . One is use of cocktails of highly targeted having different genomic mutations, and CTO treatment agents that are designed according to themolecular make -up resulted in cancers responding and demonstrating stable of the specific cancer. Another approach is to use multi - 65 disease or partial response showing tumor shrinkage . Thus targeted kinase inhibitors ( for example Sorafenib® ) . A fur - enormous efforts are directed to the development of molecu ther strategy is to use an inhibitor of several kinases that lar pharmacodynamics biomarkers of signaling outputs of US 10 , 378 , 059 B2 CTO to design combinatorial regimens against molecular The invention relates to development of molecular phar targets in different types of cancers. Current methods for macodynamics biomarkers of signaling output by transcrip assessing pathway activation in tumors involve the mea - tomic assessment of response to CTO in ex vivo cultured surement of the drug targets , known oncogenes or known human anagen hairs from human subjects with or without tumor suppressors . However , one pathway can be activated 5 cancer or other diseases. The molecular pharmacodynamics at multiple points so it is not feasible to assess pathway biomarkers of CTO expose include RAS , GFS (PI3K , PI3 / MTOR ) , MEK , HDAC , NOTCH , WNT- B catenin , HSP90 , activation by evaluating just known cancer associated genes . EGFR , P53 , CAIIPA , CAI ex vivo Calcium Signaling Non It is therefore important to develop the complete molecu voltage dependent, Calcium signaling all genes , Calcium lar signatures of CTO in view of its effect on signaling of 10 signaling ex vivo , Canonical Calcium Signaling , Canonical multiple kinases, tyrosine kinases and calcium signal trans Calcium ex vivo , Calcium all genes non - voltage dependent, duction pathways . The invention is related to evaluation of EGR1, PTEN , TGFB , CEACAMI, or Dystonin . the response of molecular pharmacodynamics markers in In a further aspect the invention provided a method of response to CTO treatment in human cell or tissue samples inhibiting RAS pathway signatures in response to treatment such as anagen hairs obtained from healthy subjects or from 15 with CTO patients , either in vivo or in vitro . In a further aspect the invention provided a method of In the in vivo model, anagen hairs are obtained before inhibiting GFS pathway signatures in response to treatment dosing the patient with CTO , and at different time points with CTO . after the daily dosing of a therapeutic amount of CTO is In a further aspect the invention provided a method of given . The patient' s clinical status and blood levels of CAI 20 inhibiting MEK pathway signatures in response to treatment are monitored during this period . with CTO . In the in vitro model the anagen hairs are obtained from In a further aspect the invention provided a method of an untreated subject and the hairs are treated in ex vivo inhibiting HDAC pathway signatures in response to treat cultures with different doses of CTO which represent the ment with CTO . range of doses required for therapeutic efficacy . 25 In a further aspect the invention provided a method of In both models, RNA is extracted from the bulbs at the inhibiting NOTCH pathway signatures in response to treat end of anagen hairs , cDNA is then prepared from the RNA ment with CTO . and global transcriptional or gene expression levels are In a further aspect the invention provided a method of determined by microarray analysis or by quantitative PCR inhibiting WNT- ß catenin pathway signatures in response to ( qPCR ) . Bioinformatic analysis is then conducted to identify 30 treatment with CTO . CTO induced gene expression changes in anagen hairs . Such In a further aspect the invention provided a method of a protocol can also be applied to issues other than anagen inhibiting HSP900 signatures in response to treatment with hair obtained from healthy subjects or patients . CTO . Accordingly , the present invention describes in greater In a further aspect the invention provided a method of detail, uses of the plucked hair biomarker assay to study 35 inhibiting EGFR pathway signatures in response to treat effects of CTO on mRNA and protein expression levels in ment with CTO . vitro . Plucked scalp hair is an ideal surrogate for measuring In a further aspect the invention provided a method of direct response to treatment with CTO . Highly vascularized , inducing P53 pathway signatures in response to treatment hair follicle can respond within hours of exposure . Given with CTO . this vascularization , their epithelial nature and rapid rate of 40 In a further aspect the invention provided a method of proliferation , the cells in the hair bulb at the base of the inhibiting genes associated with non - voltage dependent cal plucked hair and the outer root sheath are highly relevant cium signaling in response to treatment with CTO . Specifi surrogate marker tissue for solid tumors . Highly vascular - cally, the invention provides Signature Scores for the CAI ized , the hair follicle can respond to drug treatment within Ingenuity Pathway Analysis , the CAI ex vivo pathway , the hours of exposure . Bioinformatic analysis was conducted to 45 calcium signaling pathway and the canonical calcium sig identify drug - induced changes in hairs . naling pathways as pharmacodynamics markers of response to CTO . 3 . SUMMARY OF THE INVENTION In a further aspect the invention provided a method of up regulating EGR1 pathway signatures in response to treat The present invention relates to the evaluation of molecu - 50 ment with CTO . lar pharmacodynamic biomarkers of multiple signaling In a further aspect the invention provided a method of up pathways in response to CTO given in vivo or in vitro , in ex regulating PTEN pathway signatures in response to treat vivo cultured human anagen hairs . Using a commercially ment with CTO . available plucked hair molecular platform assay (Epistem In a further aspect the invention provided a method of Ltd . Manchester, UK ) direct response to treatment with 55 inducing TGF - B pathway signatures in response to treatment different doses of CTO equivalent to levels of carboxyami with CTO . dotriazole (CAI ) that are therapeutically achieved in In a further aspect the invention provided a method of patients , was evaluated to test targeting intracellular signal down regulating CEACAM1 pathway in response to treat ing pathways in oncology and other therapeutic areas. ment with CTO . Accordingly , the present invention used plucked scalp 60 In a further aspect the invention provided a method of hair from subjects , extracted the RNA from the bulbs at the down regulating dystonin pathway in response to treatment end of the anagen hairs, prepared the cDNA from the RNA , with CTO . determined the gene expression levels by microarray analy . The invention also relates to pharmaceutical compositions sis or quantitative PCR ( qPCR ) and conducted bioinformat - including CTO and another agent combined to improve ics analysis to identify drug induced gene expression 65 sensitivity and efficacy and reduce toxicity while regulating changes for CTO and other drugs, for example , Tarceva® one or more gene signatures including EGFR , MEK , VEGF, ( EGFR inhibitor ) or BEZ235 (a PI3K inhibitor ). HDAC , HSP90 , ERK , BCR - ABL , p53 , ERG1, CEACAMI, US 10 , 378 , 059 B2 dystonin or genes associates with non -voltage dependent ing : anagen hair collection from the scalp ; ex vivo culture of calcium signaling , by monitoring the molecular pharmaco the hairs for 8 and 24 hrs to different doses of CTO and to dynamics biomarkers of signaling output in response to reference dose of BEZ235 ( PI3K inhibitor ) and Tarceva CTO in ex vivo cultured anagen hairs from a treated mammal. (EGFR inhibitor) for 24 hrs only ; RNA isolation and quality In an even further aspect the invention provides a method 5 control; Epistem GentRx cDNA amplification , selection of of treating or preventing a condition in a mammal in which cDNAs passing all quality controls for 5HNVs ; sample the regulation of one or more gene signatures including labeling and microarray hybridization ; and bioinformatic EGFR , MEK , VEGF, HDAC , HSP90 , ERK , BCR - ABL , analysis using reference databases. p53 , ERG1, CEACAM1, dystonin , or genes associates with FIG . 1b describes ANOVA analysis of results of transcrip non -voltage dependent calcium signaling , prevents , inhibits tion response for all contrasts in response to different doses or ameliorates a pathology or a symptomology of the of CTO at 8 hr and 24 hr and for 1 dose of BEZ235 (PI3K condition , the method including administration of a thera inhibitor ) and Tarceva® (EGFR inhibitor ) for 24 hr only . peutically effective amount of CTO as monotherapy or as FIG . 2a illustrates the results of different doses of CTO on combinatorial therapy , and monitoring the molecular phar macodynamics biomarkers of signaling output in response to 15s multivariate signatures at 8 hr and 24 hr periods for 11 CTO in ex vivo cultured anagen hairs from a treated different signatures starting with the strongest to lowest mammal. inhibition — with EGFRI, MEKI, HSP90i, non -voltage In another aspect the present invention provides a method dependent CAI related calcium signaling , HDACI, GF and of preventing or treating a proliferative condition in a RAS, WNT/ B -catenin was inhibitory at 24 hr and no activity subject , the method including administration of a therapeu - 20 was noted for PI3KI, PI3K /mTOR , NOTCH /GSI . Impor tically effective amount of CTO alone or in combination tantly, P53 was induced and P53 stabilization was noted with another agent, and monitoring the molecular pharma - especially at 24 hr. codynamics biomarkers of signaling output in response to FIG . 26 lists 13 different signatures studied . CTO in ex vivo cultured anagen hairs from a treated FIG . 3a illustrates the Signature Score for the RAS mammal. Gene expression patterns can be established in 25 pathway in response to different doses of CTO at 8 hr and other tissues as well to distinguish between tissues in 24 hr compared with BEZ235 and Tarcevar for 24 hr. different disease states or to predict prognosis of a disease FIG . 3b illustrates the Signature Score for the Growth such as cancer in response to one or more therapies . Another paradigm is to develop a platform of pharmacodynamics Factor Signature (GFS ) pathway in response to different markers to design specific and customized formulation base doses of CTO at 8 hr and 24 hr compared with BEZ235 and on the gene expression pattern . C 30 Tarceva® for 24 hr. The invention provides a paradigm for rational selection FIG . 3c illustrates the Signature Score for the PI3K and development of combination treatments based on pathway in response to different doses of CTO at 8 hr and knowledge of the molecular abnormalities in particular 24 hr compared with BEZ235 and Tarceva for 24 hr. diseases or cancer , together with the understanding that CTO FIG . 3d illustrates the Signature Score for the PI3K / may be combined with other targeted agents that are con - 35 mTOR pathway in response to different doses of CTO at 8 structed to the molecular makeup of the disease or cancer, hr and 24 hr compared with BEZ235 and Tarceva for 24 together with the understanding that of the feedback loops hr. that apply upon blockade of a given pathway blocked by the FIG . 3e illustrates the Signature Score for the MEK targeted drug and how these feedback loops may be pre - pathway in response to different doses of CTO at 8 hr and vented , to maintain sustained inhibition of the molecular 40 24 hr compared with BEZ235 and Tarceva® for 24 hr . targets that drive the disease as well as in some instances to FIG . 4a illustrates the Signature Score for the HDAC induce suppressor genes to optimize the treatment outcome. pathway in response to different doses of CTO at 8 hr and The invention provides a shift in the method of develop - 24 hr compared with BEZ235 and Tarceva for 24 hr. ing combinatorial drug regimens inhibiting several onco - FIG . 4b illustrates the Signature Score for the NOTCH genic targets with CTO in order to overcome cancers that are 45 pathway in response to different doses of CTO at 8 hr and driven by several abnormalities , as well as to prevent or 24 hr compared with BEZ235 and Tarceva for 24 hr. neutralize the development of drug resistance by monitoring FIG . 4c illustrates the Signature Score for the WNT the pharmacodynamics biomarkers of signaling output in ß - catenin pathway in response to different doses of CTO at response to CTO and carefully picked combination drugs , by 8 hr and 24 hr compared with BEZ235 and Tarceva , for 24 transcriptomic assessment in ex vivo cultured anagen hairs . 50 hr. The current poly -pharmacology approach using several tar FIG . 4d illustrates the Signature Score for the HSP90 geted drugs cocktails has not been successful and has posed pathway in response to different doses of CTO at 8 hr and new problems due to cumulative toxicities of the drugs in the 24 hr compared with BEZ235 and Tarceva for 24 hr. cocktail . FIG . 4e illustrates the Signature Score for the EGFR An important embodiment of the invention is the devel - 55 pathway in response to different doses of CTO at 8 hr and opment of the panel of 15 - 20 gene mRNA expression 24 hr compared with BEZ235 and Tarceva for 24 hr. signatures from hair samples and deploy this on the cDNA FIG . 4f illustrates the Signature Score for the P53 pathway samples generated from patients by Affymetrix array data to in response to different doses of CTO at 8 hr and 24 hr identify genes differentially expressed in scalp hair samples compared with BEZ235 and Tarceva® for 24 hr. from untreated and treated patients . 60 FIG . 5a illustrates the Signature Score for the CAI IPA These and other features of the present teachings are set pathway in response to different doses of CTO at 8 hr and forth herein . 24 hr compared with BEZ235 and Tarceva® for 24 hr. Using the Ingenuity Pathways Analysis ( IPA ) (Ingenuity Systems, 4 . BRIEF DESCRIPTION OF FIGURES Redwood City , Calif. ) for genes influenced by CAI, some 65 suppression of CAI signature in response to CTO treatment FIG . 1a illustrates the different stages of the plucked hair was observed , except at 10 uM . When the 29 genes were biomarker platform (Epistem . Ltd .Manchester , UK ), includ - filtered from IPA for FDA < 0 . 05 and 1 . 5 FC in CTO data set , US 10 ,378 ,059 B2 to select informative genes and determine the direction of doses of CTO in vitro — this approach is not subject to change , a 14 gene set resulted . physiological conditions of absorption and delivery and was FIG . 5b illustrates the Signature Score for the CAI EX chosen . vivo pathway in response to different doses of CTO at 8 hr The understanding of cancer biology and the human and 24 hr compared with BEZ235 and Tarceva for 24 hr. 5 genome has led to the development of new classes of With the tissue specific direction of change information a targeted therapies designed to interfere with critical mol ecules and signaling pathways driving tumor growth and strong dose dependent suppression of the IPA CAI list was hold promise to improve outcomes . This is particularly observed . important for oncology therapy due to the large number of FIG . 5c illustrates the Signature Score for the Calciumof 10 approved therapies, low response rates and resistance to signaling pathway in response to different doses of CTO at many current treatments , and clinical importance of optimal 8 hr and 24 hr compared with BEZ235 and Tarceva for 24 and tailored therapy. To improve on the limitations of hr. Non -voltage dependent calcium signaling genes were cytotoxic chemotherapeutic agents , current approaches to identified from datasets in literature to inform on regulation . drug design in oncology are aimed at modulating specific FIG . 5d illustrates the Signature Score for the Calcium 1615 cell signaling pathways important for tumor growth and signaling for all gene pathways in response to differentdoses survival. In cancer cells , these pathways become deregulated of CTO at 8 hr and 24 hr compared with BEZ235 and resulting in aberrant signaling , inhibition of apoptosis , Tarceva® for 24 hr. The estimated regulation direction for increased metastasis and increased cell proliferation . all genes was identified . Though normal cells integrate multiple signaling path FIG . 5e illustrates the Signature Score for the Calcium 20 ways for controlled growth and proliferation , tumors seem Signaling pathway in response to different doses of CTO at to be heavily reliant on activation of one or two oncogene 8 hr and 24 hr compared with BEZ235 and Tarceva® for 24 pathways. Unfortunately the focus on developing new anti hr. ANOVA was used to filter informative genes ( FDR < 0 . 05 cancer therapies is not on inducing the multiple signaling and 1 . 5 FC ) . pathways that keep controlled growth or proliferation in Strong suppression of non - voltage dependent calcium 25 normal cells under control. Instead , the components of the genes was noted across CTO treatment in both literature aberrant signaling pathways represent attractive selective determined regulation and ANOVA determined set. targets for new anticancer therapies . It seems logical that FIG . 6a illustrates the Signature Score for the Canonical patients with tumors that are driven by specific oncogenic Calcium signaling using the KEGG Calcium Signaling and pathways will respond to therapeutics targeting those path IPA to predict regulation of calcium signaling in response to 30 ways . However, one pathway can be activated at multiple different doses of CTO at 8 hr and 24 hr compared with points and it is not always feasible to assess pathway BEZ235 and Tarceva for 24 hr. activation by evaluating known cancer associated genes . For FIG . 6b illustrates the Signature Score for the Canonical example , signaling through the phosphatidylinositol 3 - ki Calcium signaling ex vivo using the KEGG Calcium Sig - nase ( PI3K ) pathway is activated by multiple growth factors naling and IPA to predict regulation of in response to 35 through receptor tyrosine kinases and has effects on multiple different doses of CTO at 8 hr and 24 hr compared with processes, including cell growth and survival, metastatic BEZ235 and Tarceva® for 24 hr. Suppression noted for 6 /78 potential , and drug resistance through gene amplification canonical pathway genes only. and /or by pass or new mutations. Many pharmaceutical FIG . 7a illustrates the Signature Score for all Signaling companies are developing specific inhibitors of one or more genes after merging of the ANOVA filtered gene sets for 40 signaling pathways and proposing combinations of several both the CAI signature ( FIG . 5b ) and the non - voltage specific inhibitors to inhibit multiple oncogene pathways . dependent (NVD ) gene sets ( FIG . 5c ) . However , a major limitation to the overall benefit from FIG . 7b illustrates results in a panel of 31 CAI/ Calcium targeted therapy is the development of drug resistance . related genes capable of separating the different CTO doses , Resistance can occur because of mutations that render the both by signature view and by PCA 45 drug target insensitive to the inhibitor or when cancer cells FIG . 8 illustrates the EGR1 Signaling Pathway . change their dependency on the pathway that is targeted . In the first example , resistance can be overcome by developing 5 . DETAILED DESCRIPTION OF THE new drugs that effectively inhibit resistance -associated INVENTION mutants , as in the example of dasatinib and nilotinib which 50 are effective on BCR - ABL mutants that confer resistance to This invention is related to carboxyamidotriazole orotate imatinib . A second approach is to target multiple signaling (CTO ) , an orally active agent with antineoplastic activity , pathways simultaneously , and thus prevent the cancer from that inhibits non -voltage operated Ca2 + channels , blocking changing its dependency to another significant pathway , for both Ca2 + influx into cells and Ca2 + release from intracel example combining inhibitors of mitogen -activated protein lular stores and resulting in the disruption of calcium - 55 (MAP ) -extracellular signal regulated kinase ( ERK ) kinase mediated signal transduction and inhibition of vascular with inhibitors of PI3 kinase . The third approach is to endothelial growth factor (VEGF ) signaling , multiple tyro enhance efficacy of the targeted therapy to simultaneously sine kinase signaling , including AKT, MEK - ERK , or BCR target downstream proteins that protect tumor cells from ABL . More particularly , the present invention relates to the apoptosis . evaluation of molecular pharmacodynamics biomarkers of 60 However, a new approach to develop molecules , each of signaling output by transcriptomic assessment of response to which could modulate multiple oncogenic pathways would CTO in vivo and in vitro cultures in ex vivo cultured human be a better approach to prevent both drug resistance and anagen hairs . Anagen hairs are obtained at different time serious toxicities. This would be a much harder approach to points from subjects given varying doses of CTO treatment. design the molecule , but this approach of developing a This is the approach used in clinical trials of CTO in 65 molecule capable of modeling multiple oncogenic pathways patients . Alternately , anagen hairs are obtained from is deemed inefficient and unacceptable strategy . Yet , prob untreated subjects and the hairs are treated with varying ably the best way to inhibit several oncogenic targets in US 10 ,378 ,059 B2 10 order to overcome cancers that are driven by several naling , while inducing tumor suppressors signatures such as molecular abnormalities, as well as to prevent drug resis P53 or EGR1 in the anagen hair assay . tance and toxicity is to develop molecules that modulate A method for quantifying the response to carboxyamidotri multiple oncogenic pathways and / or induce known tumor azole orotate (CTO ) on pharmacodynamics biomarkers of suppressors . 5 multiple signature pathways , said method comprising : By using a molecule that modulates the expression of a ) Obtaining a cell sample obtained from a subject and multiple genes , and by integrating the expression data from exposing the cell sample to varying doses of CTO these multiple genes , a quantitative assessment of the gene alone , to CTO in combination with another agent or to expression signatures may be possible . These gene expres other agents for different time periods; sion signatures for pathway activation and /or inactivation 10 b ) Isolating the mRNA from the treated cell sample and may be used as i) pharmacodynamics biomarkers to monitor preparing representative cDNA there from and measur the drug induced pathway inhibition in tumors or surrogate ing the transcriptional alteration in expression in the markers such as anagen hair, ii ) as prediction biomarkers to cell sample resulting from CTO exposure ; identify tumors with high level of a particular pathway ; and c ) Calculating a signature score for each of the pharma early efficacy biomarkers to get an early readout of efficacy 15 codynamics biomarkers ofmultiple signature pathways or prevention . and quantitating the response to the varying doses of Carboxyamidotriazole orotate (CTO ) , an orotate salt of CTO exposure, selecting a list of overlapping genes carboxyamidotriazole (CAT ) is an inhibitor of receptor over expressing at two timeperiods as listed in Table 1 ; operated calcium channel- mediated calcium influx , and is and shown to have anti- proliferative and anti - invasive functions 20 d ) Identifying each of the pharmacodynamics biomarkers in several human cancer cell lines , including human glio of multiple signature pathways by at least 3 or more blastoma cells (Fiorio Pla et al, 2008 ; Ge et al, 2000 ) . By genes in a compiled list and confirming each of the interrupting calcium mobilization as a second messenger , pharmacodynamics biomarkers of multiple signature CAI can inhibit calcium - sensitive signal transduction path pathways using reference datasets . ways , including the release of arachidonic acid and its 25 RAS , Growth Factor, PI3 K Signatures metabolites; nitric oxide release ; the generation of inositol RAS gene products are involved in kinase signaling phosphates ; and tyrosine phosphorylation (Ge et al, 2000 ; pathways that control the transcription of genes, which then Kohn et al, 1992 ) . CAI inhibits phosphorylation of cellular regulate cell growth and differentiation . The conversion of proteins STATS and CrkL , and induces apoptosis in imatinib RAS from a proto - oncogene usually occurs through a point mesylate -resistant chronic myeloid leukemia cells by down - 30 mutation in the gene , and the altered function can affect the regulating bcr - abl ( Alessandro et al, 2008 ) . cell in different ways because RAS is involved in many Thus enormous efforts are directed to the development of signaling pathways that control cell division and cell death . molecular pharmacodynamics biomarkers of signaling out - Mutant ras has been identified in cancers of many origins, puts of CTO to design combinatorial regimens against including pancreas, colon , lung , thyroid , bladder ovarian , molecular targets in different types of cancers . Current 35 breast, skin , liver kidney and some leukemias . Song , S et al. , methods for assessing pathway activation in tumors involve PLOS ONE 7 : 1 - 11 ( 2012 ) . the measurement of the drug targets , known oncogenes or GFS is responsive to phosphatidylinositol 3 -kinase known tumor suppressors . However , one pathway can be (PI3K ) pathway perturbation and related to phosphatase and activated at multiple points so it is not feasible to assess tensin homolog (PTEN ) degradation . Loboda A et al. Clin pathway activation by evaluating just known cancer asso - 40 Pharm & Therap 1 : 92- 96 ( 2009 ) . ciated genes . The plucked hair biomarker assay is used to Mutations in the 1000 subunit of PI3K , called PI3KCA study effects of CTO on mRNA and protein expression are often responsible for activation of PI3K / AKT and have levels in vitro . Plucked scalp hair is an ideal surrogate for been reported in several human cancers . Janku F et al. , J Clin measuring direct response to treatment with CTO . Highly Oncol 30 :777 - 782 ( 2012 ) . vascularized , hair follicle can respond within hours of expo - 45 EGFR Pathway Signatures : sure . Given this vascularization , their epithelial nature and In a further aspect the invention provided a method of rapid rate of proliferation , the cells in the hair bulb at the inhibiting EGFR pathway signatures in response to treat base of the plucked hair and the outer root sheath are highly ment with CTO . Drugs targeting the EGF receptor ( EGFR ) relevant surrogate marker tissue for solid tumors. Bioinfor - antibodies binding the extracellular domain and small -mol matic analysis is conducted to identify drug - induced 50 ecule tyrosine kinase inhibitors have expanded treatment changes in hairs . options for several solid tumors . The EFGR gene is fre The invention relates to development of molecular phar - quently up regulated in carcinomas of the breast , kidney , macodynamics biomarkers of signaling output by transcrip - ovary , cervix , and in squamous cell carcinomas . The up tomic assessment of response to CTO in ex vivo cultured regulation is typically due to gene amplification or overex human anagen hairs from human subjects with or without 55 pression . EGFR up regulation in gliomas is most often cancer or other diseases . associated with the rearrangement of the EGFR gene result This invention provides methods , pharmacodynamics ing in alterations of its transcript so that such gliomas biomarker signatures for multiple signaling pathways in a express both wild type endogenous EGFR as well as epi cell sample such as anagen hair, in response to carboxyami- somal mutant form . The EGFR gene is amplified in > 50 % of dotriazole orotate (CTO ) from a subject. CTO has demon - 60 glioblastomas . strated response in several cancers having different genomic The EGFR -targeted monoclonal antibodies Cetuximab® mutations in clinical studies. This invention provides a and Panitumumab® have been extensively studied in meta diagnostic and prognostic assay for monitoring response to static colorectal cancers. However , the clinical efficacy of CTO ranging from - 100 fold to + 25 fold differential expres - EGFR - targeted antibodies is limited by the development of sion in several transcriptional signatures associated with 65 acquired secondary resistance which typically occurs within tumor inhibition including EGFR , MEK , HDAC , RAS , 3 to 12 months of starting therapy. Multiple mechanisms of GFS , WNT, HSP90 or non -voltage dependent calcium sig secondary resistance to anti -EGFR antibodies have been US 10 , 378 , 059 B2 reported such as expression of EGFR ligands, HER2 ampli - chaperones required for stability , post translation modifica fication , and deregulation of the EGFR recycling process . tion , and function of multiple client proteins. Expression of KRAS mutations arise and are responsible for acquired HSP is increased at times of physiologic stress , and these resistance in half the patients who initially respond to effects are believed to support cell survival. HSP90 is over cetuximab or panitumumab . Wang J et al. , Mol Cancer Ther 5 expressed in many tumor types indicating that it may play a 12 : 925- 936 (2013 ) During the past several years four EGFR inhibitors have role in the survival of cancer cells and thus making it an been approved including cetuximab , panitumumab , gefitnib attractive target for an anticancer agent . Increased HSP90 and erlotinib ( Tarceva ) and have become standard of care for has been linked to worse prognosis in patients with non use in cancer patients . However , the activity reported in 10 small cell lung cancer . Garon E B et al. , Mol Cancer Ther 12 : unselected patients has been quite limited and typically 890 - 900 (2013 ). NSCLC arises as a result of several driver develop resistance . The extent of intrinsic and acquired mutations , for example EGF receptor mutations are seen in resistance to EGFR inhibitors thus leaves ample room for about 10 % of NSCLC . HSPs play an important role in further anticancer drug development. Gou H - F et al. , PLOS neurodegenerative disorders such as Parkinson ' s disease , ONE 8 : 1 - 6 ( 2013 ) Alzheimer ' s disease or Huntington disease and therefore MEK Pathway Signatures : down regulation of HSP90 has potential beneficial effects in In a further aspect the invention provided a method of cancer and degenerative diseases . inhibiting MEK pathway signatures in response to treatment Non - voltage Dependent Calcium Signaling : with CTO . The MAPK pathway is commonly activated in In a further aspect the invention provided a method of human cancers and then activates RAF -MEK -ERK kinase 20 inhibiting genes associated with non - voltage dependent cal cascade which leads to activation downstream of substrates cium signaling in response to treatment with CTO . Kohn E involved in cell proliferation , survival, transformation , Cet al ., Cancer Res 52 : 3208 - 3212 ( 1992 ) ; Kohn EC et al. , translational control and cytoskeletal rearrangements . Tan N Proc Natl Acad Sci 92 : 1307 - 1311 ( 1995 ) Felder C F et al. , et al ., Mol Cancer Ther 12 : 853 - 864 (2013 ) . Small molecule J Phasrmacol Exp Therap 257 : 967 - 971 ( 1990 Hupe D J et inhibitors targeted this pathway , such as allosteric inhibitors 25 al. , J Biol Chem 266 : 10136 - 10142 ( 1991) ; Mignen O et al. , of MEK exhibit anticancer efficacy in vitro and in vivo . J Cell Sc 118 : 5615 - 5623 ( 2005 ) ; and Enfissi E et al. , Cell HDAC Pathway Signatures : Calcium 36 : 459 - 467 (2004 . Calcium signaling non -voltage In a further aspect the invention provided a method of dependent genes were identified and strong suppression was inhibiting HDAC pathway signatures in response to treat- noted across CTO treatment. ment with CTO . Histone acetylation is a reversible modifi - 30 Canonical calcium signaling was analyzed using the cation , with deacetylation being catalyzed by histone KEGG Calcium Signaling Pathway and IPA to predict deacetylases (HDACs ) . HDACs are represented by 18 genes regulation of canonical calcium signaling . No significant in humans and are divided into four distinct classes . Several suppression of pathway was noted . Using ANOVA to filter classes of HDAC inhibitors are being evaluated in clinical for informative genes (FDR < 0 . 05 & 1 . 5 ) it was noted that investigations and indicate that certain HDAC family mem - 35 suppression of canonical calcium genes occurred across bers are aberrantly expressed in several tumors . Unselective CTO treatment, however this only represented 7 /68 canoni HDAC inhibitors show promising results in leukemias and cal pathway genes. solid tumors , for example Vorinostat® approved for cuta TGF - B Pathway Signatures : neous T cell Lymphoma. Witt O et al. Cancer Letter 277 : In a further aspect the invention provided a method of 8 -21 (2008 ) . However, some pan -HDAC inhibitors may 40 inhibiting genes associated with TGF - B signaling in cause numerous side effects thus requiring selective target- response to treatment with CTO . TGF - B is part of a large ing of HDACs with oncogenic function in cancer cells . family of structurally related cytokines that include bone WNT Pathway Signatures : morphogenic proteins, growth and differentiation factors , In a further aspect the invention provided a method of activins and inhibins. Nearly every cell type has the ability inhibiting WNT pathway signatures in response to treatment 45 to secrete TGF - B as well as the ability to respond to TGF - B with CTO . The WNT family of signaling molecules regu - via the presence of TGF - B receptors on the cell surface . lates numerous processes in animal development, and WNT Therefore , gain or loss of function of the TGF - B pathway malfunction is implicated in various forms of disease includ - and its components are to lead to a variety of diseases ing cancer and degenerative diseases . The canonical WNT including cancer. In epithelial cells TGF - B functions as a signaling pathway is regulated at many levels and there is 50 tumor suppressor, where it inhibits proliferation , induces increasing evidence from other systems for crosstalk apoptosis and mediates differentiation . Conversely , in other between WNT signaling and other pathways important in contexts , TGF - B promotes tumor progression through tumorigenesis , converging on B - catenin . B - catenin is a increasing tumor cell invasion and metastasis . Smith A L et multifunctional protein with distinct molecular roles in cell al. , Clin Cancer Res 18 : 4514 - 4512 ( 2012 ) . adhesion at the plasma membrane and in transcription within 55 CEACAM1 Pathway Signatures : the nucleus. An increasing number of studies suggest that In a further aspect the invention provided a method of elevated WNT signaling in glioblastoma (GBM ) is initiated down regulating CEACAM1 pathway in response to treat by several alternative mechanisms that are involved in ment with CTO . CEACAM1 is a member of the carcino different steps of the disease . De Robertis A et al . , Mol embryionic antigen (CEA ) gene family of Ig - like cell - cell Cancer Ther 12 : 1180 - 1189 ( 2013 ); and Nusse R , Cell Res 60 adhesion molecules. CEACAM1 is down regulated in epi 15 : 28 - 32 (2005 ) . Therefore , inhibition of WNT signaling thelial cancers , for example prostate , bladder and colon . may represent a therapeutically relevant approach for GBM Lawson E L et al. , PLOS ONE 7 : 1 -14 ( 2012 ). treatment. Dystonin /Bpag1 Protein Signatures: HSP91 Pathway Signatures: In a further aspect the invention provided a method of In a further aspect the invention provided a method of 65 down regulating dystonin pathway in response to treatment inhibiting HSP90 pathway signatures in response to treat with CTO . Dystonin / Bpag1 proteins are cytoskeletal linkers ment with CTO . Heat shock protens serve as molecular whose loss of function in mice results in a hereditary sensory US 10 , 378 , 059 B2 13 14 neuropathy with a progressive loss of limb coordination . subject , the method including administration of a therapeu Young K et al ., Exp Cell Res 314 : 2750 - 2761 (2008 ) . tically effective amount of CTO alone or in combination P53 Pathway Signatures: with another agent, and monitoring the molecular pharma In a further aspect the invention provided a method of codynamics biomarkers of signaling output in response to inducing P53 pathway signatures in response to treatment 5 CTO in ex vivo cultured anagen hairs from a treated with CTO . Normal cells integrate multiple signaling path mammal. Gene expression patterns can be established in ways to control growth and proliferation . For example , the other tissues as well to distinguish between tissues in p53 transcription factor is a major tumor suppressor protein different disease states or to predict prognosis of a disease such as cancer in response to one or more therapies. Another that serves as a gatekeeper of cellular fate in multicellular paradigm is to develop a platform of pharmacodynamics organisms. P53 is activated in response to a variety of stress 10 markers to design specific and customized formulation base signals and initiates cell cycle arrest , senescence or apop on the gene expression pattern . tosis via pathways involving transactivation of p53 target The invention provides a paradigm for rational selection genes. Stambolic V et al. , Molecular Cell 8 :317 - 325 ( 2001 ) . and development of combination treatments based on This universal protection of genetic integrity is however knowledge of the molecular abnormalities in particular impaired in many human cancers . 15 diseases or cancer, together with the understanding that CTO In a further aspect the invention provided a method of up may be combined with other targeted agents that are con regulating P53 pathway signatures in response to treatment structed to the molecular makeup of the disease or cancer, with CTO . Mutations of PTEN are frequently found in a together with the understanding that of the feedback loops variety of cancers including brain , breast , endometrial, pros - that apply upon blockade of a given pathway blocked by the tate and kidney tumors . PTEN is a tumor suppressor and is 20 targeted drug and how these feedback loops may be pre a negative regulator of PI3K /PKB /AKT - dependent cellular vented , to maintain sustained inhibition of the molecular survival . targets that drive the disease as well as in some instances to EGR1 Pathway Signatures : induce suppressor genes to optimize the treatment outcome. In a further aspect the invention provided a method of up The invention provides a shift in the method of develop regulating EGR1 pathway signatures in response to treat- 25 ing combinatorial drug regimens inhibiting several onco ment with CTO . The early growth response 1 ( EGR1) gene genic targets with CTO in order to overcome cancers that are product is a transcription factor with roles in differentiation driven by several abnormalities, as well as to prevent or and growth . The transcription factor EGR1 is a direct neutralize the development of drug resistance by monitoring regulator of multiple tumor suppressor including TGFpi , the pharmacodynamics biomarkers of signaling output in PTEN , and fibronectin . Baron V et al. , Cancer gene Therapy 30 response to CTO and carefully picked combination drugs, by 13 : 115 - 124 ( 2006 ) . In certain human tumor cells and tissues transcriptomic assessment in ex vivo cultured anagen hairs . EGR1 exhibits prominent tumor suppressor function and The current poly -pharmacology approach using several tar many human tumor cell lines express little or no EGR1 in geted drugs cocktails has not been successful and has posed contrast to their normal counterparts . EGR1 is decreased to new problems due to cumulative toxicities of the drugs in the undetectable in non small cell lung cancers, breast tumors 35 cocktail . The invention provides a rescue solution for tar and human gliomas. Reexpression of ERG 1 in human tumor geted and non - targeted drug combinations that fail due to cell lines inhibits transformation . The mechanism of sup drug resistance mechanisms by combining them with CTO pression involves the direct induction of TGF -B1 leading to from the start or even after drug resistance is noted , to increased fibronectin , and plasminogen activator inhibitor. maintain sincitivity and effectiveness. Liu , C et al Proc Natl Acad Sci 93 : 11831 - 11836 ( 1996 ) . 40 An important embodiment of the invention is the devel EGR1 is implicated in the regulation of P53 in melanoma opment of the panel of up to 15 - 20 gene mRNA expression cells leading to apoptosis and the proapoptotic suppressor signatures from hair samples and deploy this on the cDNA gene PTEN is also directly regulated by EGR1. samples generated from patients by Affymetrix array data to The invention also relates to pharmaceutical compositions identify genes differentially expressed in scalp hair samples including CTO and another agent combined to improve 45 from untreated and treated patients . sensitivity and efficacy and reduce toxicity while regulating It is an objective of the present invention to evaluate one or more gene signatures including EGFR ,MEK , VEGF, molecular pharmacodynamic markers in response to car HDAC , HSP90 , ERK , BCR - ABL , p53 , ERG1, CEACAMI, boxyamidotriazole orotate ( CTO ) in ex vivo human anagen dystonin , or genes associates with non - voltage dependent hairs obtained from subjects . CTO is an orally active agent calcium signaling , by monitoring the molecular pharmaco - 50 with antineoplastic activity , that inhibits non - voltage oper dynamic biomarkers of signaling output in response to CTO ated Ca2 + channels , blocking both Ca2 + influx into cells and in ex vivo cultured anangen hairs from a treated mammal. Ca2 + release from intracellular stores and resulting in the In an even further aspect the invention provides a method disruption of calcium -mediated signal transduction and inhi of treating or preventing a condition in a mammal in which bition of vascular endothelial growth factor (VEGF ) signal the regulation of one or more gene signatures including 55 ing , multiple tyrosine kinase signaling , including AKT, EGFR , MEK , VEGF , HDAC , HSP90 , ERK , BCR - ABL , MEK - ERK , or BCR - ABL . More particularly , the present p53, ERG1, CEACAM1, dystonin , or genes associates with invention relates to the evaluation of molecular pharmaco non - voltage dependent calcium signaling , prevents , inhibits dynamics biomarkers of signaling output by transcriptomic or ameliorates a pathology or a symptomology of the assessment of response to CTO in ex vivo cultured human condition , the method including administration of a thera - 60 anagen hairs . peutically effective amount of CTO as monotherapy or as combinatorial therapy , and monitoring the molecular phar 6 . EXAMPLES macodynamics biomarkers of signaling output in response to CTO in ex vivo cultured anangen hairs from a treated Example 1 mammal . 65 In another aspect the present invention provides a method The plucked hair biomarker platform developed by of preventing or treating a proliferative condition in a Epistem Ltd (Manchester , United Kingdom ) was used to US 10 ,378 ,059 B2 15 16 assess transcriptomic response to CTO in ex vivo cultured probes than CTO or BEZ235 at this threshold . For CTO human anagen hairs . FIG . la describes the overall process differential probes increased in a dose related manner. CTO steps . showed the greatest effect transcriptionally in anagen hair at Plucked scalp hair is an ideal surrogate for measuring all doses compared with BEZ235 or Tarceva® ) . Results are direct response to CTO treatment. It is a non - invasive and 5 presentedpor in detail in FIG . 16 . Biologically relevant altera can also be used using samples from patients who have been tion of the hair bulb transcriptome ranging from - 100 fold treated with CTO , in which case the hairs do not need to be to + 25 fold differential expression was observed at clinically treated ex vivo . Hairs growing on the scalp in growth stage relevant levels of CTO . (anagen ) and which have highly vascularized follicles are Example 2 suitable . 10 Donor hairs were plucked from 5 male donor volunteers , The signature scores were assessed as described in detail immediately transferred to maintenance medium cultures by Loboda A ., et al (Clinical Pharmacology & Therapeutics and exposed to varying doses of CTO equivalent to 2 M , 5 86 : 92 - 96 (2009 ) for identification of growth factor gene uM , and 10 uM carboxyamidotriazole (CAI ) . The cultures 15 signatures, and by Loboda A et al, BMC Medical Genomics were either maintained for 8 hrs or 24 hrs . Controls were 3 : 1 - 11 (2010 ) for identification of signatures of RAS used , for example , Tarceva? . (EGFR inhibitor ) at 1 uM and pathway and PI3K . These references are incorporated BEZ235 ( PI3K inhibitor ) at 1 uM for 24 hrs only. Once in herein . They describe the Ingenuity Pathway Analysis ( Inge culture hairs were collected at the specified periods for n uity Systems, Redwood City , Calif. ) ; http : / /www . ingenu mRNA isolation or protein analysis to ensure quality con - . ity. com software tool to identify signaling pathways that are trol. Small amounts of RNA ( about up to 500 ng ) are statistically enriched among growth factor signature genes. extracted from the bulbs at the end of the anagen hairs . The RAS pathway was analyzed using publicly available Representative cDNA was prepared from the RNA and gene and literature datasets , e . g ., https :/ array. nci . nih .gov /carray / expression levels determined by microarray analysis . Biotin project/ woost - 00041. labeling , fragmentation and hybridization to 048 Affymetrix 35 . The results obtained for probes observed at the two time U133 plus 2 . 0 array was done . Bioinformatic analysis was periods were: 1440 at 8 hours and 2961 at 24 hrs. A high done to identify CTO induced gene expression changes . The degree overlap was observed between the 2 lists (39 % , whole procedure is given in FIG . 1 . p < 0 .0001 ) . The net result was 558 probes (442 unique Results obtained show strong transcriptional response for annotated genes, ranging - 75 to + 33 fold at high dose all contrasts . High level of differential expression of tran CTO / 24 hr. Significant results of Signature Scores are pre scripts was observed . Tarceva? showed less differential sented graphically . The Probe List is presented in Table 1 . TABLE 1 Probeset ID Entrez Gene Gene Symbol Gene Title 222450 _ at 56937 PMEPA1 prostate transmembrane protein , androgen induced 1 233565 _ s _ at 100528031 III 27111 FKBP1A -SDCBP2 / / / FKBP1A - SDCBP2 SDCBP2 readthrough ( non - protein coding ) // / syndecan binding protein (syntenin ) 242832 _ at 5187 PER1 period homolog 1 ( Drosophila ) 240463 at 213039 _ at 23370 ARHGEF18 Rho /Rac guanine nucleotide exchange factor (GEF ) 18 235072 _ s _ at 63971 KIF13A kinesin family member 13A 208926 _ at 4758 NEU1 sialidase 1 ( lysosomal sialidase ) 237444 _ at 239451 _ at 222288 _ at 227579 _ at 2241 FER fer ( fps / fes related ) tyrosine kinase 212717 _ at 9842 PLEKHM1 pleckstrin homology domain containing, family M ( with RUN domain ) member 1 226853 at 55589 BMP2K BMP2 inducible kinase 214112 _ s _ at 541578 // / 91966 CXorf40A // / CXorf40B chromosome X open reading frame 40A / / / chromosome X open reading frame 40B 209012 _ at 7204 TRIO triple functional domain (PTPRF interacting) 219476 _ at 79098 Clorf116 chromosome 1 open reading frame 116 238086 _ at 100129617 LOC100129617 uncharacterized LOC100129617 230721 _ at 730094 C16orf52 chromosome 16 open reading frame 52 1566079 _ at 647190 RPS16P5 ribosomal protein S16 pseudogene 5 223839 _ s _ at 6319 SCD stearoyl -CoA desaturase ( delta 9 - desaturase ) 225671 at 124976 SPNS2 spinster homolog 2 (Drosophila ) US 10 ,378 ,059 B2 17 18 TABLE 1 - continued Probeset ID Entrez Gene Gene Symbol Gene Title 212961 _ x _ at 541578 CXorf40B chromosome X open reading frame 40B 223659 _ at 84000 TMPRSS13 transmembrane protease , serine 13 229909 _ at 283358 B4GALNT3 beta - 1 , 4 - N -acetyl galactosaminyl transferase 3 223467 _ at 51655 RASD1 RAS , dexamethasone - induced 235146 _ at 57458 TMCC3 transmembrane and coiled - coil domain family 3 235548 _ at 164284 APCDDIL adenomatosis polyposis coli down -regulated 1 - like 206816 _ s _ at 26206 SPAG8 sperm associated antigen 8 242323 _ at 81579 PLA2G12A phospholipase A2, group XIIA 224579 _ at 81539 SLC38A1 solute carrier family 38 , member 1 213315 _ x _ at 91966 CXorf40A chromosome X open reading frame 40A 227314 _ at 3673 ITGA2 integrin , alpha 2 ( CD49B , alpha 2 subunit of VLA - 2 receptor ) 227093 _ at 57602 USP36 Ubiquitin specific peptidase 36 200760 _ s _ at 10550 ARL6IP5 ADP - ribosylation - like factor 6 interacting protein 5 201790 _ s _ at 1717 DHCR7 7 -dehydrocholesterol reductase 1554980 _ a _ at 467 ATF3 activating transcription factor 3 242255 _ at 22884 WDR37 WD repeat domain 37 219267 _ at 51228 GLTP glycolipid transfer protein 1555786 _ s _ at 645687 LINC00520 long intergenic non -protein coding RNA 520 229734 _ at 283174 LOC283174 uncharacterized LOC283174 242856 _ at 201037 _ at 5214 PFKP phosphofructokinase , platelet 1562970 _ at 201465 _ s _ at 3725 JUN jun proto - oncogene 202067 _ s _ at 3949 LDLR low density lipoprotein receptor 223679 _ at 1499 CTNNB1 catenin ( cadherin -associated protein ) , beta 1 , 88 kDa 201235 _ s _ at 7832 BTG2 BTG family , member 2 225662 _ at 51776 ZAK sterile alpha motif and leucine zipper containing kinase AZK 204401 _ at 3783 KCNN4 potassium intermediate /small conductance calcium - activated channel , subfamily N , member 222906 _ at 28982 FLVCR1 feline leukemia virus subgroup C cellular receptor 1 238613 _ at 51776 ZAK sterile alpha motif and leucine zipper containing kinase AZK 206414 _ s _ at 8853 ASAP2 ArfGAP with SH3 domain , ankyrin repeat and PH domain 2 210794 _ s _ at 55384 MEG3 maternally expressed 3 (non protein coding ) 226621 _ at 9180 OSMR oncostatin M receptor 230682 _ x _ at 8714 ABCC3 ATP -binding cassette , sub family C (CFTR /MRP ) , member 3 235668 at 639 PRDM1 PR domain containing 1 , with ZNF domain 205483 _ s _ at 9636 ISG15 ISG15 ubiquitin - like modifier 215808 _ at 5655 KLK10 kallikrein - related peptidase 10 212281 _ s _ at 27346 TMEM97 transmembrane protein 97 212282 _ at 27346 TMEM97 transmembrane protein 97 226287 _ at 91057 CCDC34 coiled - coil domain containing 34 213618 at 116984 ARAP2 ArfGAP with RhoGAP domain , ankyrin repeat and PH domain 2 231089 _ at 100505664 LOC100505664 uncharacterized LOC100505664 227140 _ at 3624 INHBA inhibin , beta A 231467 at 202967 _ at 2941 GSTA4 glutathione S -transferase alpha 230323 _ s _ at 120224 TMEM45B transmembrane protein 45B 224471 _ S _ at 8945 BTRC beta - transducin repeat containing E3 ubiquitin protein ligase US 10 ,378 ,059 B2 19 20 TABLE 1 - continued Probeset ID Entrez Gene Gene Symbol Gene Title 202708 _ s _ at 8349 HIST2H2BE histone cluster 2 , H2be 242871 _ at 54852 PAQR5 progestin and adipo receptor family member V 205627 _ at 978 CDA cytidine deaminase 235542 _ at 200424 TET3 tet methylcytosine dioxygenase 240410 _ at 236656 _ s _ at 100288911 LOC100288911 uncharacterized LOC100288911 206164 at 9635 CLCA2 chloride channel accessory 2 203159 _ at 2744 GLS glutaminase 224991 _ at 80790 CMIP C -Maf inducing protein 204258 _ at 1105 CHD1 chromodomain helicase DNA binding protein 1 228249 _ at 119710 Cilorf74 chromosome 11 open reading frame 74 229013_ at 145783 LOC145783 uncharacterized LOC145783 211547 _ s _ at 5048 PAFAH1B1 platelet - activating factor acetylhydrolase 1b , regulatory subunit 1 ( 45 kDa ) 226863 _ at 642273 FAM110C family with sequence similarity 110 , member 208161 _ s _ at 8714 ????? ATP -binding cassette , sub family C (CFTR /MRP ) , member 3 214805 _ at 1973 EIF4A1 eukaryotic translation initiation factor 4A1 229429 _ x _ at 728855 // / 728875 LOC728855 // / uncharacterized LOC728855 // / LOC728875 uncharacterized LOC728875 202720 _ at 26136 TES testis derived transcript ( 3 LIM domains ) 224995 _ at 56907 SPIRE1 spire homolog 1 (Drosophila ) 214771 _ x _ at 23164 MPRIP myosin phosphatase Rho interacting protein 201939 _ at 10769 PLK2 polo - like kinase 2 238587 _ at 84959 UBASH3B ubiquitin associated and SH3 domain containing B 232113 _ at 208690 _ s _ at 9124 PDLIM1 PDZ and LIM domain 1 201464 _ x _ at 3725 JUN jun proto - oncogene 236657 _ at 100288911 LOC100288911 uncharacterized LOC100288911 215541 _ S _ at 1729 DIAPH1 diaphanous homolog 1 (Drosophila ) 238028 _ at 647024 C6orf132 chromosome 6 open reading frame 132 226893 _ at ABL2 V -abl Abelson murine leukemia viral oncogene homolog 2 237576 _ x _ at 100506480 LOC100506480 uncharacterized LOC100506480 1552256 _ a _ at 949 SCARB1 scavenger receptor class B , member 1 215255 _ at 22997 IGSF9B immunoglobulin superfamily , member 9B 1557258 _ a _ at 8915 BCL10 B -cell CLL /lymphoma 10 240623 _ at 228754 _ at 6533 SLC6A6 solute carrier family 6 ( neurotransmitter transporter , taurine ), member 6 217257 _ at 6452 SH3BP2 SH3- domain binding protein 2 241036 _ at 242553 _ at 8714 ABCC3 ATP -binding cassette , sub family C (CFTK /MRP ) , member 3 239358 _ at 210868 _ s _ at 79071 ELOVL6 ELOVL fatty acid elongase 6 200815 _ s _ at 5048 PAFAH1B1 platelet- activating factor acetylhydrolase 1b , regulatory subunit 1 (45 kDa) 208436 _ s _ at 3665 IRF7 interferon regulatory factor 7 208138 _ at 2520 GAST gastrin 241780 _ at 200730 _ s _ at 7803 PTP4A1 protein tyrosine phosphatase type IVA , member 1 219697 _ at 9956 HS3ST2 heparan sulfate ( glucosamine ) 3 - O - sulfotransferase 2 201693 _ s _ at 1958 EGR1 early growth response 1 218847 _ at 10644 IGF2BP2 insulin - like growth factor 2 mRNA binding protein 2 230469 _ at 219790 RTKN2 rhotekin 2 US 10 ,378 ,059 B2 21 TABLE 1 - continued Probeset ID Entrez Gene Gene Symbol Gene Title 209917 _ s _ at 11257 TP53 TG1 TP53 target 1 (non -protein coding) 224329 _ s _ at 84518 CNFN cornifelin 212253 __ x _ at 100652766 / / / 667 DST / / / LOC100652766 dystonin / / / dystonin - like 238058 _ at 150381 LOC150381 uncharacterized LOC150381 239334 _ at 57488 ESYT2 Extended synaptotagmin - like protein 2 222271 at 216718 _ at 388699 LINC00302 long intergenic non - protein coding RNA 302 219076 _ s _ at 5827 PXMP2 peroxisomal membrane protein 2 , 22 kDa 204475 _ at 4312 MMP1 matrix metallopeptidase 1 ( interstitial collagenase ) 221185 _ s _ at 84223 IQCG IQ motif containing G 203586 _ s _ at 379 ARL4D ADP - ribosylation factor - like 4D 217802 _ s _ at 64710 NUCKS1 nuclear casein kinase and cyclin - dependent kinase substrate 1 205767 _ at 2069 EREG epiregulin 228360 _ at 130576 LYPD6B LY6 / PLAUR domain containing 6B 228917 _ at 228748 _ at 966 CD59 CD59 molecule , complement regulatory protein 219632 _ s _ at 23729 / / / 7442 SHPK III TRPV1 sedoheptulokinase // / transient receptor potential cation channel, subfamily V , member 238715 _ at 646014 LOC646014 Uncharacterized LOC646014 218810 _ at 80149 ZC3H12A zinc finger CCCH - type containing 12A 225177 _ at 80223 RAB11 FIP1 RAB11 family interacting protein 1 ( class I) 224454 _ at 55500 ETNK1 ethanolamine kinase 1 209498 at 634 CEACAM1 carcinoembryonic antigen related cell adhesion molecule 1 (biliary glycoprotein ) 1557257 _ at 8915 BCL10 B - cell CLL /lymphoma 10 225133 _ at 51274 KLF3 Kruppel- like factor 3 (basic ) 202340 _ x _ at 3164 NR4A1 nuclear receptor subfamily 4 , group A , member 1 1556545 _ at 212474 _ at 23080 AVL9 AVL9 homolog ( S . cerevisiase ) 210241 _ s _ at 11257 TP53 TG1 TP53 target 1 (non -protein coding) 243543 at 239132 at 4842 NOS1 nitric oxide synthase 1 ( neuronal) 222757 _ s _ at 51776 ZAK sterile alpha motif and leucine zipper containing kinase AZK 201194 _ at 6415 SEPW1 selenoprotein W , 1 229874 _ x _ at 100506687 LOC100506687 uncharacterized LOC100506687 202557 _ at 6782 HSPA13 heat shock protein 70 kDa family , member 13 239669 _ at 231907 _ at 27 ABL2 v -abl Abelson murine leukemia viral oncogene homolog 2 229074 _ at 30844 EHD4 EH - domain containing 4 205428 _ s _ at 794 CALB2 calbindin 2 205822 _ s _ at 3157 HMGCS1 3 -hydroxy - 3 -methylglutaryl COA synthase 1 (soluble ) 210869 _ s _ at 4162 MCAM melanoma cell adhesion molecule 225665 _ at 51776 ZAK sterile alpha motif and leucine zipper containing kinase AZK 212781_ at 5930 RBBP6 retinoblastoma binding protein 232355 _ at 767579 SNORD114 - 3 small nucleolar RNA , C / D box 114 - 3 213288 _ at 129642 MBOAT2 membrane bound O acyltransferase domain containing 2 221666 _ s _ at 29108 PYCARD PYD and CARD domain containing 203072 _ at 4643 MYO1E myosin IE 215465 _ at 26154 ABCA12 ATP -binding cassette , sub famiiy A (ABC1 ) , member 12 US 10 ,378 ,059 B2 23 24 TABLE 1 -continued Probeset ID Entrez Gene Gene Symbol Gene Title 224453 _ s _ at 55500 ETNK1 ethanolamine kinase 1 216935 _ at 388699 LINC00302 long intergenic non -protein coding RNA 302 209086 _ x _ at 4162 MCAM melanoma cell adhesion molecule 218833 _ at 51776 ZAK sterile alpha motif and leucine zipper containing kinase AZK 209377 _ s _ at 9324 HMGN3 high mobility group nucleosomal binding domain 3 223519 _ at 51776 ZAK sterile alpha motif and leucine zipper containing kinase AZK 210138 _ at 8601 RGS20 regulator of G -protein signaling 20 1558845 _ at 100506089 LOC100506089 uncharacterized LOC100506089 201819 _ at 949 SCARB1 scavenger receptor class B , member 1 204310 _ s _ at 4882 NPR2 natriuretic peptide receptor B / guanylate cyclase B ( atrionatriuretic peptide receptor B 239377 _ at 84285 EIF1AD eukaryotic translation initiation factor 1A domain containing 224611 _ s _ at 80331 DNAJC5 DnaJ ( Hsp40 ) homolog , subfamily C , member 5 219155 _ at 26207 PITPNC1 phosphatidylinositol transfer protein , cytoplasmic 1 227163 _ at 119391 GSTO2 glutathione S - transferase omega 2 209633 _ at 5523 PPP2R3A protein phosphatase 2 , regulatory subunit B " , alpha 219681 _ s _ at 80223 RAB11 FIP1 RAB11 family interacting protein 1 ( class I ) 221860 _ at 3191 HNRNPL heterogeneous nuclear ribonucleoprotein L 243296 _ at 10135 NAMPT Nicotinamide phosphoribosyltransferase 237133 _ at 1556000 _ s _ at 55727 BTBD7 BTB (POZ ) domain containing 204681 _ s _ at 9771 RAPGEF5 Rap guanine nucleotide exchange factor (GEF ) 5 215726 _ s _ at 1528 CYB5A cytochrome b5 type A (microsomal ) 210886 _ x _ at 11257 TP53 TG1 TP53 target 1 (non -protein coding) 226597 _ at 92840 REEP6 receptor accessory protein 6 204995 _ at 8851 CDK5R1 cyclin - dependent kinase 5 , regulatory subunit 1 (p35 ) 236119 _ s _ at 6706 SPRR2G small proline- rich protein 2G 219228 _ at 55422 ZNF331 zinc finger protein 331 234971 _ x _ at 113026 PLCD3 phospholipase C , delta 3 201127 _ s _ at 47 ACLY ATP citrate lyase 226880 _ at 64710 NUCKS1 Nuclear casein kinase and cyclin - dependent kinase substrate 1 209383 _ at 1649 DDIT3 DNA - damage - inducible transcript 3 204168 _ at 4258 MGST2 microsomal glutathione S transferase 2 239670 _ at 65268 WNK2 WNK lysine deficient protein kinase 2 208512 _ s _ at 4301 MLLT4 myeloid / lymphoid or mixed lineage leukemia ( trithorax homolog, Drosophila ) ; translocate 213281 _ at 3725 JUN Jun proto -oncogene 218310 _ at 154881 / / / 27342 KCTD7 / / / RABGEF1 potassium channel tetramerisation domain containing 7 / // RAB guanine nucleotide exchan 205151 _ s _ at 9865 TRIL TLR4 interactor with leucine rich repeats 218217 _ at 59342 SCPEP1 serine carboxypeptidase 1 205055 _ at 3682 ITGAE integrin , alpha E (antigen CD103 , human mucosal lymphocyte antigen 1 ; alpha polypeptide US 10 ,378 ,059 B2 25 26 TABLE 1 - continued Probeset ID Entrez Gene Gene Symbol Gene Title 215009 _ s _ at 100499177 THAP9 - AS1 THAP9 antisense RNA 1 ( non protein coding ) 227484 _ at 57522 SRGAP1 SLIT -ROBO Rho GTPase activating protein 1 239769 _ at 1009 CDH11 Cadherin 11, type 2 , OB cadherin ( osteoblast ) 230360 _ at 342035 GLDN gliomedin 227112 _ at 23023 TMCC1 transmembrane and coiled - coil domain family 1 201482 _ at 5768 QSOX1 quiescin Q6 sulfhydryl oxidase 210337 _ s _ at 47 ACLY ATP citrate lyase 203911_ at 5909 RAPIGAP RAP1 GTPase activating protein 206683 _ at 7718 ZNF165 zinc finger protein 165 202935 _ s _ at 6662 SOX9 SRY ( sex determining region Y ) -box 9 218951 _ s _ at 55344 PLCXD1 phosphatidylinositol- specific phospholipase C , X domain containing 1 233488 _ at 84659 RNASET ribonuclease , RNase A family , 202562 _ s _ at 11161 C14orfi chromosome 14 open reading frame 1 208745 _ at 10632 ATP5L ATP synthase , H + transporting , mitochondrial Fo complex , subunit G 236078 _ at 57707 KIAA1609 KIAA1609 226226 _ at 120224 TMEM45B transmembrane protein 45B 213854 _ at 9145 SYNGR1 synaptogyrin 1 243955 _ at 222111 _ at 54629 FAM63B family with sequence similarity 63 , member B 1560296 _ at 240038 _ at 211372 _ s _ at 7850 IL1R2 interleukin 1 receptor , type II 202672 _ s _ at 467 ATF3 activating transcription factor 3 218717 _ s _ at 55214 LEPREL1 leprecan - like 1 228366 _ at 230516 _ at 115416 MALSU1 Mitochondrial assembly of ribosomal large subunit 1 201920 _ at 6574 SLC20A1 solute carrier family 20 (phosphate transporter) , member 1 209632 _ at 5523 PPP2R3A protein phosphatase 2 , regulatory subunit B " , alpha 207367 _ at 479 ATP12A ATPase , H + / K + transporting , nongastric , alpha polypeptide 1557256 _ a _ at 200811_ at 1153 CIRBP cold inducible RNA binding protein 205201 _ at 2737 GLI3 GLI family zinc finger 3 227724 _ at 728190 LOC728190 uncharacterized LOC728190 205403 _ at 7850 IL1R2 interleukin 1 receptor , type II 242827 _ x __ at 228084 _ at 81579 PLA2G12A phospholipase A2 , group XIIA 209365 _ s _ at 1893 ECM1 extracellular matrix protein 1 243279 _ at 224946 _ s _ at 84317 CCDC115 coiled - coil domain containing 115 218708 at 29107 NXT1 NTF2- like export factor 1 1560531 _ at 353132 LCE1B late cornified envelope 1B 207761 _ s _ at 25840 METTL7A methyltransferase like 7A 206011 _ at 834 CASP1 caspase 1 , apoptosis- related cysteine peptidase 213703 _ at 150759 LINC00342 long intergenic non -protein coding RNA 342 224595 _ at 23446 SLC44A1 solute carrier family 44 , member 1 224613 _ s _ at 80331 DNAJC5 DnaJ (Hsp40 ) homolog , subfamily C , member 5 212504 _ at 22982 DIP2C DIP2 disco - interacting protein 2 homolog C ( Drosophila ) 213682 _ at 10762 NUP50 nucleoporin 50 kDa 205247 _ at 4855 NOTCH4 notch 4 228235 _ at 84848 MGC16121 uncharacterized protein MGC16121 242873 _ at US 10 ,378 ,059 B2 27 28 TABLE 1 -continued Probeset ID Entrez Gene Gene Symbol Gene Title 205960 _ at 5166 PDK4 pyruvate dehydrogenase kinase , isozyme 4 230494 _ at 6574 SLC20A1 solute carrier family 20 (phosphate transporter) , member 1 221260 _ s _ at 81566 CSRNP2 cysteine- serine- rich nuclear protein 2 224480 _ s _ at 84803 AGPAT9 1 -acylglycerol - 3 -phosphate O acyltransferase 9 210180 _ s _ at 6434 TRA2B transformer 2 beta homolog ( Drosophila ) 204621_ s _ at 4929 NR4A2 nuclear receptor subfamily 4 , group A , member 2 217863 _ at 8554 PIAS1 protein inhibitor of activated STAT, 1 236423 _ at 223421 _ at 50626 CYHR1 cysteine / histidine -rich 1 220272 at 54796 BNC2 basonuclin 2 201791 _ S _ at 1717 DHCR7 7 - dehydrocholesterol reductase 215574 _ at 224328 _ s _ at 84648 LCE3D late cornified envelope 3D 211828 _ s _ at 23043 TNIK TRAF2 and NCK interacting kinase 58367 _ s _ at 79744 ZNF419 zinc finger protein 419 218950 _ at 64411 ARAP3 ArfGAP with RhoGAP domain , ankyrin repeat and PH domain 3 1552703 _ s _ at 114769 / // 834 CARD16 / / / CASP1 caspase recruitment domain family , member 16 / // caspase 1 , apoptosis - related cysteine 219687 _ at 55733 HHAT hedgehog acyltransferase 232127 _ at 1184 CLCN5 chloride channel , voltage sensitive 5 218377 _ s _ at 10069 RWDD2B RWD domain containing 2B 210335 _ at 9182 RASSF9 Ras association ( RalGDS/ AF 6 ) domain family ( N -terminal ) member 9 227927 _ at 227224 _ at 55103 RALGPS2 Ral GEF with PH domain and SH3 binding motif 2 224778 _ s _ at 57551 TAOK1 TAO kinase 1 229566 _ at 645638 LOC645638 WDNM1- like pseudogene 202734 _ at 9322 TRIP10 thyroid hormone receptor interactor 10 201851_ at 6455 SH3GL1 SH3- domain GRB2- like 1 237337 _ at 37152 _ at 5467 PPARD peroxisome proliferator activated receptor delta 209687 _ at 6387 CXCL12 chemokine ( C - X - C motif ) ligand 12 203152 _ at 64976 MRPL40 mitochondrial ribosomal protein L40 201627 _ s _ at 3638 INSIG1 insulin induced gene 1 232593 _ at 93082 NEURL3 neuralized homolog 3 (Drosophila ) pseudogene 224769 _ at 57551 TAOK1 TAO kinase 1 209702 _ at 79068 FTO fat mass and obesity associated 204546 _ at 9764 KIAA0513 KIAA0513 232224 _ at 5648 MASP1 mannan -binding lectin serine peptidase 1 (C4 /C2 activating component of Ra -reactive fac 239930 _ at 2590 GALNT2 UDP - N - acetyl- alpha - D galactosamine: polypeptide N acetylgalactosaminyltransferase 2 (Gal 203178 _ at 2628 GATM glycine amidinotransferase ( L arginine :glycine amidinotransferase ) 235782 _ at 218181 _ s _ at 9448 MAP4K4 mitogen -activated protein kinase kinase kinase kinase 4 233520 _ s _ at 202333 CMYA5 cardiomyopathy associated 5 213456 _ at 25928 SOSTDCi sclerostin domain containing 1 219528 _ s _ at 64919 BCL11B B - cell CLL/ lymphoma 11B ( zinc finger protein ) 224945 _ at 55727 BTBD7 BTB (POZ ) domain containing US 10 ,378 ,059 B2 29 30 TABLE 1 -continued Probeset ID Entrez Gene Gene Symbol Gene Title 214866 _ at 5329 PLAUR plasminogen activator, urokinase receptor 209941 _ at 8737 RIPK1 receptor ( TNFRSF ) - interacting serine - threonine kinase 1 226029 _ at 57216 VANGL2 vang- like 2 (van gogh , Drosophila ) 212596 _ s _ at 10042 HMGXB4 HMG box domain containing 4 229873 _ at 283219 KCTD21 potassium channel tetramerisation domain containing 21 226392 at 5922 RASA2 RAS p21 protein activator 2 226005 _ at 7326 UBE2G1 ubiquitin - conjugating enzyme E2G 1 214445 _ at 22936 ELL2 elongation factor, RNA polymerase II , 2 227680 _ at 284695 ZNF326 zinc finger protein 326 227786 _ at 90390 MED30 mediator complex subunit 30 222067 _ x _ at 3017 HIST1H2BD histone cluster 1 , H2bd 1569106 _ s _ at 55209 SETD5 SET domain containing 5 231785 _ at 4909 NTF4 neurotrophin 4 223937 _ at 27086 FOXP1 forkhead box P1 1558685 _ a _ at 158960 LOC158960 uncharacterized protein BC009467 211965 _ at 677 ZFP36L1 zinc finger protein 36 , C3H type - like 1 39549 _ at 4862 NPAS2 neuronal PAS domain protein 2 203800 _ s _ at 63931 MRPS14 mitochondrial ribosomal protein S14 1556321 _ a _ at 212321 _ at 8879 SGPL1 sphingosine - 1 - phosphate lyase 222154 _ s _ at 26010 SPATS2L spermatogenesis associated , serine - rich 2 - like 218774 _ at 28960 DCPS decapping enzyme, scavenger 212268 at 1992 SERPINB1 serpin peptidase inhibitor, clade B (ovalbumin ), member 1 213134 _ x _ at 10950 BTG3 BTG family , member 3 230669 _ at 5922 RASA2 RAS p21 protein activator 2 1559901 _ s _ at 388815 LINC00478 long intergenic non -protein coding RNA 478 225298 _ at 25953 PNKD paroxysmal nonkinesigenic dyskinesia 242558 _ at 226043 _ at 26086 GPSM1 G - protein signaling modulator 210236 _ at 8500 PPFIA1 protein tyrosine phosphatase , receptor type , f polypeptide ( PTPRF ) , interacting protein 214066 _ x _ at 4882 NPR2 natriuretic peptide receptor B /guanylate cyclase B (atrionatriuretic peptide receptor B 240024 _ at 23541 SEC14L2 SEC14 - like 2 ( S . cerevisiae ) 235462 _ at 132864 CPEB2 Cytoplasmic polyadenylation element binding protein 2 1554015 _ a _ at 1106 CHD2 chromodomain helicase DNA binding protein 2 235347 _ at 84859 LRCH3 leucine - rich repeats and calponin homology (CH ) domain containing 3 230847 _ at 56897 WRNIP1 Werner helicase interacting protein 1 201427 _ s _ at 6414 SEPP1 selenoprotein P , plasma, 1 1557905 _ s _ at 960 CD44 CD44 molecule ( Indian blood group ) 219084 _ at 64324 NSD1 nuclear receptor binding SET domain protein 1 206176 _ at 654 BMP6 bone morphogenetic protein 6 219826 _ at 79744 ZNF419 zinc finger protein 419 212356 _ at 23351 KHNYN KH and NYN domain containing 218909 _ at 26750 RPS6KC1 ribosomal protein S6 kinase, 52 kDa, polypeptide 1 230555 _ s _ at 90390 MED30 Mediator complex subunit 30 212687 _ at 3987 LIMS1 LIM and senescent cell antigen - like domains 1 203098 _ at 9425 CDYL chromodomain protein , Y - like US 10 ,378 ,059 B2 31 TABLE 1 - continued Probeset ID Entrez Gene Gene Symbol Gene Title 229054 _ at 677 ZFP36L1 zinc finger protein 36 , C3H type - like 1 236039 _ at 284348 LYPD5 LY6 /PLAUR domain containing 5 209661 _ at 3801 KIFC3 kinesin family member C3 209560 _ s _ at 8788 DLK1 delta - like 1 homolog ( Drosophila ) 225812 _ at 619208 Coorf225 chromosome 6 open reading frame 225 227829 _ at 120071 GYLTLIB glycosyltransferase - like 1B 238623 _ at 229415 _ at 54205 CYCS cytochrome c , somatic 209222 _ s _ at 9885 OSBPL2 oxysterol binding protein - like 2 1555809 _ at 83716 CRISPLD2 cysteine -rich secretory protein LCCL domain containing 2 204567 _ s _ at 9619 ABCG1 ATP -binding cassette , sub family G (WHITE ) , member 1 232277 _ at 64078 SLC28A3 solute carrier family 28 ( sodium -coupled nucleoside transporter ) , member 3 237197 _ at 225209 _ s _ at 118424 UBE2J2 ubiquitin -conjugating enzyme E2 , J2 231916 _ at 4842 NOS1 nitric oxide synthase 1 ( neuronal) 212279 _ at 27346 TMEM97 transmembrane protein 97 204862 _ s _ at 4832 NME3 NME /NM23 nucleoside diphosphate kinase 3 230483 _ at - 212856 _ at 23151 GRAMD4 GRAM domain containing 4 224650 _ at 114569 MAL2 mal, T - cell differentiation protein 2 (gene / pseudogene) 202963 _ at 5993 RFX5 regulatory factor X , 5 ( influences HLA class II expression ) 225320 _ at 90550 MCU mitochondrial calcium uniporter 236274 _ at 8662 EIF3B eukaryotic translation initiation factor 3 , subunit B 209780 _ at 57157 PHTF2 putative homeodomain transcription factor 2 218823 _ s _ at 54793 KCTD9 potassium channel tetramerisation domain containing 9 227787 _ s _ at 90390 MED 30 mediator complex subunit 30 230296 _ at 730094 C16orf52 chromosome 16 open reading frame 52 222892 _ s _ at 55287 TMEM40 transmembrane protein 40 210610 _ at 634 CEACAM1 carcinoembryonic antigen related cell adhesion molecule 1 ( biliary glycoprotein ) 230031 _ at 3309 HSPA5 heat shock 70 kDa protein 5 ( glucose - regulated protein , 78 kDa ) 238477 _ at 10749 KIF1C kinesin family member 10 209409 _ at 2887 GRB10 growth factor receptor- bound protein 10 217995 _ at 58472 SQRDL sulfide quinone reductase- like ( yeast ) 226873 _ at 54629 FAM63B family with sequence similarity 63 , member B 1553722 _ s _ at 220441 RNF152 ring finger protein 152 204710 _ s _ at 26100 WIPI2 WD repeat domain , phosphoinositide interacting 2 212653 _ s _ at 23301 EHBP1 EH domain binding protein 1 203979 _ at 1593 CYP27A1 cytochrome P450 , family 27 , subfamily A , polypeptide 1 244350 _ at 4651 MYO10 myosin X 223233 Sat 57530 CGN cingulin 1555967 _ at 214355 _ x _ at 100128553 / / / CTAGE15P // / CTAGE family , member 15 , 100142659 / / / CTAGE4 / / / pseudogene / // CTAGE family , 340307 // / CTAGEOP // / member 4 / / / CTAGE family , 441294 // / 643854 CTAGE8 / // CTAGES member 214469 _ at 3012 // / 8335 HIST1H2AB // / histone cluster 1 , H2ab / // HIST1H2AE histone cluster 1 , H2ae US 10 ,378 ,059 B2 33 34 TABLE 1 -continued Probeset ID Entrez Gene Gene Symbol Gene Title 212472 _ at 9645 MICAL2 microtubule associated monoxygenase , calponin and LIM domain containing 2 228115 _ at 64762 FAM59A family with sequence similarity 59 , member A 228964 _ at 639 PRDM1 PR domain containing 1 , with ZNF domain 230027 _ s _ at 84545 MRPL43 mitochondrial ribosomal protein L43 207318 _ s _ at 8621 CDK13 cyclin - dependent kinase 13 221689 _ s _ at 51227 PIGP phosphatidylinositol glycan anchor biosynthesis , class P 219270 _ at 79094 CHAC1 ChaC, cation transport regulator homolog 1 ( E . coli ) 225299 _ at 4645 MYO5B myosin VB 239770 _ at 83850 ESYT3 extended synaptotagmin - like protein 3 226399 _ at 79982 DNAJB14 DnaJ (Hsp40 ) homolog , subfamily B , member 14 226656 _ at 10491 CRTAP cartilage associated protein 228852 _ at 2029 ENSA endosulfine alpha 206239 _ s _ at 6690 SPINK1 serine peptidase inhibitor, Kazal type 1 210993 _ s _ at 4086 SMAD1 SMAD family member 1 238462 _ at 84959 UBASH3B ubiquitin associated and SH3 domain containing B 211962 _ s _ at 677 ZFP36L1 zinc finger protein 36 , C3H type - like 1 224666 _ at 197370 NSMCE1 non -SMC element 1 homoiog ( S . cerevisiae ) 239028 _ at 130574 LYPD6 LY6 / PLAUR domain containing 6 213577 _ at 6713 SOLE squalene epoxidase 202011_ at 7082 TJP1 tight junction protein 1 (zona occludens 1 ) 212254 _ s _ at 100652766 // / 667 DST / // LOC100652766 dystonin // / dystonin - like 221701 _ s _ at 64220 STRA6 stimulated by retinoic acid gene 6 homolog (mouse ) 239576 _ at 57509 MTUSI microtubule associated tumor suppressor 1 234418 _ x _ at 960 CD44 CD44 molecule ( Indian blood group ) 227985 _ at 100506098 LOC100506098 uncharacterized LOC100506098 213462 _ at 4862 NPAS2 neuronal PAS domain protein 2 224975 _ at 4774 NFIA nuclear factor I/ A 225990 _ at 91653 BOC Boc homolog (mouse ) 240616 _ at 219911 sat 28231 SLCO4A1 solute carrier organic anion transporter family , member 4A1 224970 _ at 4774 NFIA nuclear factor I/ A 214623 _ at 26226 FBXW4P1 F -box and WD repeat domain containing 4 pseudogene 1 239478 _ x _ at 55668 C14orf118 chromosome 14 open reading frame 118 226909 _ at 85460 ZNF518B zinc finger protein 518B 208670 _ s _ at 23741 EID1 EP300 interacting inhibitor of differentiation 1 206192 _ at 1041 CDSN corneodesmosin 222173 _ s _ at 55357 TBC1D2 TBC1 domain family , member 228450 _ at 144100 PLEKHAT pleckstrin homology domain containing , family A member 7 1558097 _ at 253143 PRR14L proline rich 14 - like 219373 at 54344 DPM3 dolichyl -phosphate mannosyltransferase polypeptide 3 230388 _ s _ at 644246 KANSL1- AS1 KANSL1 antisense RNA 1 (non -protein coding) 207098 _ s _ at 55669 MFN1 mitofusin 1 223484 _ at 84419 C15orf48 chromosome 15 open reading frame 48 244804 _ at 8878 SOSTM1 sequestosome 1 229679 _ at 400073 C12orf76 chromosome 12 open reading frame 76 225826 _ at 326625 MMAB methylmalonic aciduria ( cobalamin deficiency ) cbIB type US 10 ,378 ,059 B2 35 36 TABLE 1 -continued Probeset ID Entrez Gene Gene Symbol Gene Title 213352 _ at 23023 TMCC1 transmembrane and coiled - coil domain family 1 211883 _ x _ at 634 CEACAM1 carcinoembryonic antigen related cell adhesion molecule 1 ( biliary glycoprotein ) 210387 _ at 8339 // / 8343 / / / HIST1H2BC III histone cluster 1 , H2bc // / 8344 / / / 8346 / / / 8347 HIST1H2BE / / / histone cluster 1 , H2be / / / HIST1H2BF / / / histone cluster 1 , H2bf / // HIST1H2BG / / / his HIST1H2BI 210916 _ s _ at 960 CD44 CD44 molecule ( Indian blood group ) 221432 _ s _ at 81894 SLC25A28 solute carrier family 25 (mitochondrial iron transporter) , member 28 218487 _ at 210 ALAD aminolevulinate dehydratase 223264 _ at 59274 MESDC1 mesoderm development candidate 1 206356 _ S _ at 2774 GNAL guanine nucleotide binding protein ( G protein ), alpha activating activity polypeptide , 218097 _ s _ at 79004 CUEDC2 CUE domain containing 2 228001 at 757 TMEM50B transmembrane protein 50B 212441 _ at 9778 KIAA0232 KIAA0232 201854 _ s _ at 23300 ATMIN ATM interactor 121 at 7849 PAX8 paired box 8 222143 _ s _ at 64419 MTMR14 myotubularin related protein 14 1558002 _ at 11171 STRAP Serine /threonine kinase receptor associated protein 226040 _ at 226141 _ at 91050 CCDC149 coiled - coil domain containing 149 1556567 _ at 4676 NAP1. 4 nucleosome assembly protein 1 - like 4 226263 _ at 154007 SNRNP48 small nuclear ribonucleoprotein 48 kDa (U11 /U12 ) 212074 _ at 23353 SUN1 Sad1 and UNC84 domain containing 1 227387 _ at 54780 NSMCE4A Non - SMC element 4 homolog A ( S . cerevisiae) 232795 _ at — 203936 _ s _ at 4318 MMP9 matrix metallopeptidase 9 (gelatinase B , 92 kDa gelatinase, 92 kDa type IV collagenase ) 225033 _ at 6482 STUGAL1 ST3 beta - galactoside alpha - 2 , 3 sialyltransferase 1 209109 _ s _ at 7105 TSPAN6 tetraspanin 6 213351 _ s _ at 23023 TMCC1 transmembrane and coiled - coil domain family 1 203047 _ at 6793 STK10 serine / threonine kinase 10 220721 _ at 80110 ZNF614 zinc finger protein 614 1556127 _ at 23181 DIP2A DIP2 disco - interacting protein 2 homolog A (Drosophila ) 215016 _ x _ at 100652766 // / 667 DST / // LOC100652766 dystonin / // dystonin - like 206576 _ s _ at 634 CEACAM1 carcinoembryonic antigen related cell adhesion molecule 1 (biliary glycoprotein ) 240674 _ at 3720 JARID2 jumonji , AT rich interactive domain 2 225646 _ at 1075 CTSC cathepsin C 1554010 _ at 3340 NDST1 N -deacetylase / N sulfotransferase (heparan glucosaminyl) 1 204100 _ at 7067 THRA thyroid hormone receptor, alpha 221840 _ at 5791 PTPRE protein tyrosine phosphatase , receptor type , E 209078 _ s _ at 25828 TXN2 thioredoxin 2 218530 _ at 29109 FHOD1 formin homology 2 domain containing 1 235434 at 230063 at 9422 ZNF264 zinc finger protein 264 40420 _ at 6793 STK10 serine /threonine kinase 10 221027 _ s _ at 81579 PLA2G12A phospholipase A2 , group XIIA 244202 _ at 212108 at 23197 FAF2 Fas associated factor family member 2 US 10 ,378 ,059 B2 37 38 TABLE 1 - continued Probeset ID Entrez Gene Gene Symbol Gene Title 204294 _ at 275 AMT aminomethyltransferase 225503 at 207063 DHRSX dehydrogenase / reductase ( SDR family ) X - linked 212810 _ s _ at 6509 SLC1A4 solute carrier family 1 ( glutamate/ neutral amino acid transporter) , member 4 214814 _ at 91746 YTHDC1 YTH domain containing 1 228468 _ at 84930 MASTL microtubule associated serine / threonine kinase - like 209108 _ at 7105 TSPAN6 tetraspanin 6 220444 _ at 79230 ZNF557 zinc finger protein 557 206172 _ at 3598 IL13RA2 interleukin 13 receptor , alpha 2 225002 _ s _ at 25870 SUMF2 sulfatase modifying factor 2 212205 _ at 94239 H2AFV H2A histone family, member V 228851 _ s _ at 2029 ENSA endosulfine alpha 209048 _ s _ at 23613 ZMYNDS zinc finger , MYND - type containing 8 211846 _ s _ at 5818 PVRL1 poliovirus receptor- related 1 ( herpesvirus entry mediator C ) 238909 _ at 6281 S100A10 S100 calcium binding protein A10 205503 _ at 5784 PTPN14 protein tyrosine phosphatase , non -receptor type 14 243829 _ at 673 BRAF V -raf murine sarcoma viral oncogene homolog B1 244379 _ at 223251 _ s _ at 55608 ANKRD10 ankyrin repeat domain 10 202633 _ at 11073 TOPBP1 topoisomerase ( DNA ) II binding protein 1 214502 _ at 8970 HIST1H2BJ histone cluster 1 , H2bj 221773 _ at 2004 ELK3 ELK3 , ETS -domain protein ( SRF accessory protein 2 ) 41858 _ at 27315 PGAP2 post -GPI attachment to proteins 212850 _ s _ at 4038 LRP4 low density lipoprotein receptor- related protein 4 223408 _ s _ at 214472 _ at 3013 II / 8350 // / HIST1H2AD / / / histone cluster 1 , H2ad / // 8351 / / / 8352 / / / HIST1H3A / II histone cluster 1 , H3a // / 8353 / / / 8354 / / / HIST1H3B / / / histone cluster 1, H3b // / 8355 / / / 8356 / / / HIST1H3C / / / histo 8357 / / / 8358 / HIST1H3D // / HIST1H3E / / / HIST1H3F / / / HIST1H3G / / / HIST1H3H // / HIST1H3I / // HIST1H3J 225647 s _ at 1075 CTSC cathepsinc 1559977 _ a _ at 284723 SLC25A34 solute carrier family 25 , member 34 211347 _ at 8555 CDC14B CDC14 cell division cycle 14 homolog B ( S . cerevisiae ) 1558208 _ at 227570 _ at 144110 TMEM86A transmembrane protein 86A 227492 _ at 100506658 / // 647859 LOC647859 / // OCLN occludin pseudogene // / occludin 1558778 _ s _ at 57496 MKL2 MKL /myocardin - like 2 31637 _ s _ at 7067 / / / 9572 NR1D1 / / / THRA nuclear receptor subfamily 1 , group D , member 1 / // thyroid hormone receptor , alpha 229190 _ at 100507376 LOC100507376 uncharacterized LOC100507376 236188 _ s _ at 4676 NAP1L4 Nucleosome assembly protein 1 - like 4 212503 _ s _ at 22982 DIP2C DIP2 disco - interacting protein 2 homolog C ( Drosophila ) 204760 _ s _ at 7067 / / / 9572 NR1D1 / // THRA nuclear receptor subfamily 1 , group D ,member 1 / // thyroid hormone receptor, alpha 212099 _ at 388 RHOB ras homolog family member B 214873 _ at 91355 LRP5L low density lipoprotein receptor- related protein 5 - like 228181 _ at 7779 SLC30A1 solute carrier family 30 (zinc transporter ) , member 1 212763 _ at 23271 CAMSAP2 calmodulin regulated spectrin associated protein family , member 2 US 10 ,378 ,059 B2 39 40 TABLE 1 - continued Probeset ID Entrez Gene Gene Symbol Gene Title 226285 _ at 4076 CAPRIN1 cell cycle associated protein 1 213567 _ at 3840 K???4 karyopherin alpha 4 ( importin alpha 3 ) 203927 _ at 4794 NFKBIE nuclear factor of kappa light polypeptide gene enhancer in B - cells inhibitor , epsilon 208523 x _ at 8339 // / 8343 // / HIST1H2BC // / histone cluster 1 , H2bc / // 8344 // / 8346 / // 8347 HIST1H2BE / / / histone cluster 1 , H2be / / / HIST1H2BF / / / histone cluster 1, H2bf // / HIST1H2BG / / / his HIST1H2BI 219389 _ at 55061 SUSD4 sushi domain containing 4 202329 _ at 1445 CSK C -src tyrosine kinase 238523 _ at 79786 KLHL36 kelch -like 36 (Drosophila ) 1565016 _ at 3276 PRMT1 protein arginine methyltransferase 1 226409 _ at 128637 TBC1D20 TBC1 domain family , member 20 229926 _ at 100500850 MIR3682 microRNA 3682 208527 _ x _ at 8339 / / / 8343 / / / HIST1H2BC / / / histone cluster 1 , H2bc // / 8344 / / / 8346 / / / 8347 HIST1H2BE / / / histone cluster 1 , H2be / // HIST1H2BF // / histone cluster 1 , H2bf / / / HIST1H2BG / / / his HIST1H2BI 223598 _ at 5887 RAD23B RAD23 homolog B ( S . cerevisiae ) 243797 _ at 9262 STK17B serine/ threonine kinase 17b 203317 _ at 23550 PSD4 pleckstrin and Sec7 domain containing 4 230965 _ at 9099 USP2 ubiquitin specific peptidase 2 208490 _ x _ at 8339 // / 8343 / // HIST1H2BC III histone cluster 1 , H2bc // / 8344 / // 8346 // / 8347 HIST1H2BE / / / histone cluster 1 , H2be / / / HIST1H2BF / / histone cluster 1 , H2bf // / HIST1H2BG / / / his HIST1H2BI 235514 _ at 151516 ASPRV1 aspartic peptidase , retroviral like 1 209098 _ s _ at 182 JAG1 jagged 1 1554229 _ at 153222 CREBRF CREB3 regulatory factor 209398 _ at 3006 HIST1H1C histone cluster 1 , Hic 202629 _ at 10513 APPBP2 amyloid beta precursor protein ( cytoplasmic tail) binding protein 2 203428 _ s _ at 25842 ASF1A ASF1 anti- silencing function 1 homolog A ( S . cerevisiae ) 238005 _ S _ at 25942 SIN?? SIN3 transcription regulator homolog A (yeast ) 214455 _ at 8339 / // 8343 / // HIST1H2BC / // histone cluster 1 , H2bc / // 8344 / / / 8346 / / / 8347 HIST1H2BE / / / histone cluster 1 , H2be / // HIST1H2BF / / / histone cluster 1 , H2bf // / HIST1H2BG / / / his HIST1H2BI 214073 _ at 2017 CTTN cortactin 203140 _ at 604 BCL6 B -cell CLL / lymphoma 6 232150 _ at 208546 _ x _ at 8345 HIST1H2BH histone cluster 1 , H2bh 243446 _ at 84962 AJUBA ajuba LIM protein 236207 _ at 6744 SSFA2 sperm specific antigen 2 212016 _ s _ at 5725 PTBP1 polypyrimidine tract binding protein 1 232311 _ at 567 B2M Beta - 2 -microglobulin 219711 at 54807 ZNF586 zinc finger protein 586 208579 _ x _ at 5 4145 // / 85236 H2BFS // / HIST1H2BK H2B histone family, member S ( pseudogene ) // / histone cluster 1 , H2bk 239493 _ at 6129 RPL7 ribosomal protein L7 214074 _ s _ at 2017 CTTN cortactin 228091 at 55014 STX17 syntaxin 17 234331 _ s _ at 151354 FAM84A family with sequence similarity 84 , member A 212372 _ at 4628 MYH10 myosin , heavy chain 10 , non muscle US 10 , 378 , 059 B2 42 Using the probe list in Table 1 , a multivariate analysis of NOTCH pathway in response to different doses of CTO at different signatures was conducted using available refer - 8 hr and 24 hr is compared with BEZ235 and Tarceva? for ences to build the following signatures, to analyze the results 24 hr. at different doses of CTO ( equivalent to 2 UM , 5 uM , and 10 uM CAI) at 8 hrs and 24 hrs: - RAS signature ; Growth factor 5 FIG . 4c describes results showing WNT ß - catenin signa signature ; PI3K /mTOR inhibition ; PI3K inhibition ; MEK ture showsmodes suppression in 24 hrs exposure to CTO . inhibition ; HSP90 inhibition ; HDAC inhibition : EGFR inhi The Signature Score for the WNT B -catenin pathway in bition : P53 Stabilization : WNT/ B -Catenin inhibition ; Cal- response to different doses of CTO at 8 hr and 24 hr is cium Signaling; CAI inhibition ; canonical calcium inhibi compared with BEZ235 and Tarceva® for 24 hr . tion ; and Non - voltage signaling . 10 FIG . 4d describes strong suppression of HSP90 signature Results obtained for the above analyses are summarized with CTO treatment which is dose dependent. The Signature in FIG . 2b in detail . EGFR , MEK and HDAC pathways were strongly suppressed in response to CTO . Score for the HSP90 pathway in response to different doses In contrast , the pathway associated with P53 was stabi of CTO at 8 hr and 24 hr is compared with BEZ235 and lized in response to CTO . Tarceva® for 24 hr. Denondent 15 FIG . 4e describes very strong suppression of EGFR In addition , genes associated with non - voltage dependent 15 signature. F with CTO treatment and importantly this is stron calcium signaling, were strongly suppressed . These results ger than that in Tarceva? at all doses of CTO and time are discussed in detail below . points. The Signature Score for the EGFR pathway in Example 3 response to different doses of CTO at 8 hr and 24 hr is 20 compared with BEZ235 and Tarceva® for 24 hr FIG . 3a describes results of multivariate signatures for FIG . 4f describes induction of P53 signature with CTO RAS and Growth Factor Signatures. Briefly , modest down treatment at all doses which is higher at the 24 hr time point . regulation in RAS and Growth Factor signatures (GFS ) were The Signature Score for the P53 pathway in response to observed , the inhibition being most obvious at 8 hrs. Table different doses of CTO at 8 hr and 24 hr is compared with 2 gives List of RAS and GFS signatures . BEZ235 and Tarceva? for 24 hr. TABLE 2 GFS And RAS : Symbol ABCC5 CYHR1 HIST3H2A POU2F3 COROIC IFRD1 PFKP ATP6V1B1 DEPTOR HOXB13 RAMP DLEU2 IMPAD1 PNPT1 ATXN3 DNAL4 ING4 SEMA3G DPH3 KLK6 PSMC4 BCAS1 EIF4A2 OVGP1 SEPP1 EIF5 K???4 RPS6KA3 BCL2L11 EPHX2 PCMTD1 SIDT2 ENO2 LRP8 S100A2 CALCOCO1 ERBB3 PCMTD2 AREG HN1 MALL SERPINB5 CAPN13 HIST1H2AC PDIA4 BTG3 HSP90AA1 MTHFDIL SERPINB8 CRBN HIST1H2BD PLEKHG4 CEBPG HSPAL PADI1 SLC7A1 SRXN1 TIPIN

FIG . 3c describes results on PI3K in response to CTO . 40 Example 5 Strong suppression of PI3K signature was observed with control BEZ235 treatment but not with CTO . FIG . 3d describes results on PI3K /mTOR signature. FIG . 5a illustrates the Signature Score for the CAI IPA Strong suppression of PI3K /mTOR signature was observed pathway in response to different doses of CTO at 8 hr and with control BEZ235 treatment but not with CTO . 45 24 hr compared with BEZ235 and Tarceva® for 24 hr. Using FIG . 3e describes strong inhibition of MEKi signature in the Ingenuity Pathways Analysis (IPA ) ( Ingenuity Systems, all CTO treatments at 8 hrs and 24 hrs . Redwood City , Calif. ) for genes influenced by CAI, some suppression of CAI signature in response to CTO treatment Example 4 was observed , except at 10 uM . When the 29 genes were 50 filtered from IPA for FDA < 0 .05 and 1 . 5 FC in CTO data set , FIG . 4a gives results showing weak suppression of to select informative genes and determine the direction of HDAC signature in response to CTO treatment. The Signa - change , a 14 gene set resulted . TABLE 3 lists the CAI IPA : Symbol MMP2 ESR1FOS PCLG2 MAPK6 MAP15 AKTI MOS3 HSP90B1 JUN CCND1 PPAR1 MAPK1 MAPK7 CASP3 AKT2 HSP90AA1 Hsp84 - 2 CEBPA MAPK3 PCLG1 MAPK4 MAPK12 HSPAS AKT3 HSP90AB1 Hsp84 - 3 BAG3 ture Score for the HDAC pathway in response to different FIG . 5b illustrates the Signature Score for the CAI Ex doses of CTO at 8 hr and 24 hr is compared with BEZ235 vivo pathway in response to different doses of CTO at 8 hr and 24 hr compared with BEZ235 and Tarceva? for 24 hr. and Tarceva® for 24 hr. 65 With the tissue specific direction of change information a FIG . 4b describes no suppression of Notch signature in strong dose dependent suppression of the IPA CAI list was response to CTO treatment . The Signature Score for the observed . Table 4 lists the 14 gene set . US 10 ,378 ,059 B2 43 44 TABLE 4 Symbol: AKT2 CASP3 FOS HSP90AB1 JUN CEBPA MAPK3 BAG3 CCND1 HSP90AA1 HSP90B1 AKT1 MAPK1 MAPK7

FIG . 5c illustrates the Signature Score for the Calcium signaling pathway in response to different doses of CTO at 8 hr and 24 hr compared with BEZ235 and Tarceva for 24 10 hr. Non - voltage dependent calcium signaling genes were identified from datasets in literature to inform on regulation . The list is presented in Table 5 .

TABLE 5 15 Symbol : ARG2 CCNA CCND2 CCNE2 TNF CAI BDNF CCNA2 CCNE1 CTF1 BRAF CALR 20 FIG . 5d illustrates the Signature Score for the Calcium signaling for all gene pathway in response to different doses of CTO at 8 hr and 24 hr compared with BEZ235 and Tarceva for 24 hr. The estimated regulation direction for all genes was identified . The list is provided in Table 6 . TABLE 6 Symbol : ARG2 CCND2 TNF PPP3R1 CALM3 CAMK2A CAMK4 ORAI3 TRPC3 TRPC7 BDNF CCNE1 PPP3CA PPP3R2 CAMK1 CAMK2B NOS2STIM1 TRPC4 BRAF CCNA1 CCNE2 PPP3CB CALM1 CAMK1D CAMK2D ORAI1 STIM2 TRPC5 CA9 CCNA2 CTF1 PPP3CC CALM2 CAMK1G CAMK2G ORAI2 TRPCI TRPC6 CALR

FIG . 5e illustrates the Signature Score for the Calcium 35 Signaling pathway in response to different doses of CTO at 8 hr and 24 hr compared with BEZ235 and Tarceva® for 24 hr. ANOVA was used to filter informative genes ( FDR < 0 .05 and 1. 5 FC ) . Strong suppression of non - voltage dependent calcium 40 genes was noted across CTO treatment in both literature determined regulation and ANOVA determined set. Table 7 . TABLE 7 Symbol : BDNF CCNE1 PPP3CC ORAI3 TNF CAMK1 ORAI1 BRAF CCNA1 PPP3CB CAMK2D CCND2 CALM3 CAMK2G STIM2 CALR

FIG . 6a illustrates the Signature Score for the Canonical SO Calcium signaling using the KEGG Calcium Signaling and TABLE 8 -continued IPA to predict regulation of calcium signaling in response to Symbol different doses of CTO at 8 hr and 24 hr compared with CACNAID CHRNA2 GRIK1 HDACI BEZ235 and Tarceva® for 24 hr. Table 8 . 55 CACNA1F CHRNA3 GRIN1 HTR3A CACNA1G CHRNA4 GRIN2A RYR1 TABLE 8 CACNA1H CHRNA5 GRIN2B SLC8A1 CACNALI CHRNA6 GRIN2C TNNC1 Symbol CACNAIS CHRNAZ GRIN2D CHRNAS PPP3?? CACNA2D4 CHRNB3 HDAC10 CACNA2D1 GRINJA PPP3CB CACNB1 CHRNB4 HDAC11 60 CACNA2D2 CHRNB1 GRIN3B PPP3CC CACNB2 CHRND HDAC2 CACNA2D3 CHRNB2 HDAC1 PPP3R1 CACNB3 CHRNE HDAC3 PPP3R2 CACNB4 CHRNG HDAC4 ATP2C1 CACNG1 GRIA1 HDAC5 FIG . 6b illustrates the Signature Score for the Canonical CACNA1A CHRFAMIA GRIA2 HDAC6 CACNA1B CHRNA1 GRIA3 HDAC7 65 Calcium signaling ex vivo using the KEGG Calcium Sig CACNAIC CHRNA10 GRIA4 HDAC8 naling and IPA to predict regulation of in response to MITTITEdifferent doses of CTO at 8 hr and 24 hr compared with US 10 , 378 ,059 B2 45 46 BEZ235 and Tarceva® for 24 hr. Suppression noted for 6 /78 Dystonin was down regulated by 60 fold in response to canonical pathway genes only. Table 9 CTO treatment. TABLE 9 Gene Symbol: HDAC3 HDAC4 PPP3CC GRIA3 CACNB3 HDAC8 PPP3CC HDAC4 PPP3CB ATP2C1 GRIA3 GRIA3 PPP3CC PPP3CC

10 Example 7 TGF - B signaling was inhibited in response to treatment with CTO . FIG . 7a illustrates the Signature Score for all Signaling W ! The present invention is not to be limited in scope by the genes after merging of the ANOVA filtered gene sets for embodiment disclosed in the example which is intended as both the CAI signature (FIG . 5b ) and the non - voltage 15 an illustration of one aspect of the invention and any dependent (NVD ) gene sets (FIG . 5c ) . methods which are functionally equivalent are within the FIG . 7b illustrates results in a panel of 31 CAI/ Calcium scope of the invention . Indeed , various modifications of the related genes capable of separating the different CTO doses , invention in addition to those shown and described herein both by signature view and by PCA . Table 10 provides the will become apparent to those skilled in the art from the list of 31 genes. 20 foregoing description . Such modifications are intended to fall within the scope of the appended claims. TABLE 10 Those skilled in the art will recognize, or be able to Gene Symbol Source ascertain using no more than routine experimentation , any equivalents to the specific embodiments of the invention AKT1 CAI AKT2 CAI 25 described herein . Such equivalents are intended to be BAG3 CAI encompassed by the claims. CASP3 CAI CCND1 CAI What is claimed is : CEBPA CAI 1 . A method for quantifying the response to carboxyami FOS CAI dotriazole orotate (CTO ) on more than one signature path HSP90AA1 CAI 30 way wherein said signature pathways are RAS ,GFS , MEKI, HSP90AB1 CAI HDAC , NOTCH , WNTB - catenin , HSP90 , EGFR , p53 , HSP90B1 CAI JUN CAI EGR1, CEACAMI, TGFB or Dystonin and on pharmaco MAPK1 CAI dynamic biomarkers for each of said signature pathways , MAPK3 CAI said method comprising : MAPK7 CAI 35 a ) obtaining a cell sample obtained from a subject and BDNF Non - voltage BRAF Non - voltage treating cultures of the cell sample with varying doses CALM3 Non - voltage of CTO alone , and maintaining the cultures for different CALR Non - voltage time periods ; CAMK1 Non - voltage b ) isolating the mRNA from the treated cultures of the cell CAMK2D Non - voltage 40 CAMK2G Non - voltage sample obtained in step a ), and preparing representative CCNA1 Non - voltage cDNA therefrom , and measuring the transcriptional CCND2 Non - voltage alteration in expression in the treated cultures of the CCNE1 Non - voltage cell sample ; ORAI1 Non - voltage c ) calculating a signature score for each of the pharma ORAI3 Non - voltage 45 PPP3CB Non - voltage codynamics biomarkers of each of said signature path PPP3CC Non - voltage ways using the Ingenuity Pathway Analysis ( IPA ) Sys STIM2 Non - voltage tem and quantitating the response to the varying doses TNF Non - voltage ATP2C1 KEGG of CTO , and selecting a list of overlapping genes CACNB3 KEGG expressing after 8 hours and 24 hours of exposure to GRIA3 KEGG 50 CTO based on the calculated signature scores, from the HDAC3 KEGG list consisting of: HDACH KEGG

Results of bioinformatic analysis of data obtained in Probeset ID Entrez Gene Gene Symbol response to varying doses of CTO at 8 hr and 24 hrs indicate 55 - 222450 _ at 56937 PMEPA1 that the early growth response 1 gene product ( EGR1) was 233565 _ s _ at 100528031 / 1 / 27111 FKBP1A - SDCBP2 / / / up regulated 6 fold by CTO treatment. In contrast EGR1 was SDCBP2 suppressed by BEZ235 and Tarceva® . The up regulation of 242832 _ at 5187 PER1 EGR1 generally regulates multiple tumor suppressor path 240463 _ at ways inducing apoptotic downstream events . Liu , C et al 60 213039 _ at 23370 ARHGEF18 235072 _ s _ at 63971 KIF13A Proc Natl Acad Sci 93 : 11831 - 11836 ( 1996 ) . 208926 at 4758 NEU1 FIG . 8 illustrates the EGR1 Signaling Pathway 237444 _ at 239451 at — Example 8 222288 _ at 227579 _ at 2241 FER The carcinoembryonic antigen - related cell adhesion mol- 65 212717 at 9842 PLEKHM1 ecule (CEACAM1 ) (also known as CD66a) was down 226853 _ at 55589 BMP2K regulated in response to both CTO and Tarceva® treatment. US 10 ,378 ,059 B2 47 48 - continued - continued 214112 _ s _ at 541578 / / / 91966 CXorf40A / II 232113 _ at CXorf40B 208690 _ s _ at 9124 PDLIM1 209012 _ at 7204 TRIO 201464 _ x _ at 3725 JUN 219476 _ at 79098 Clorf116 236657 _ at 100288911 LOC100288911 238086 _ at 100129617 LOC100129617 215541 _ s _ at 1729 DIAPH1 230721 at 730094 C16orf52 238028 _ at 647024 C6orf132 1566079 _ at 647190 RPS16P5 226893 _ at 27 ABL2 223839 _ s _ at 6319 SCD 237576 _ x _ at 100506480 LOC100506480 225671 _ at 124976 SPNS2 1552256 _ a _ at 949 SCARB1 212961 _ x _ at 541578 CXorf40B 10 215255 at 22997 IGSF9B 223659 _ at 84000 TMPRSS13 1557258 _ a _ at 8915 BCL10 229909 _ at 283358 B4GALNT3 240623 _ at 223467 _ at 51655 RASD1 228754 at 6533 SLC6A6 235146 _ at 57458 TMCC3 217257 _ at 6452 SH3BP2 235548 _ at 164284 APCDDIL 241036 at 206816 s at 26206 SPAG8 242553 at 8714 ABCC3 242323 _ at 81579 PLA2G12A 239358 _ at 224579 at 81539 SLC38A1 210868 _ s _ at 79071 ELOVL6 213315 _ x _ at 91966 CXorf40A 200815 _ s _ at 5048 PAFAH1B1 227314 _ at 3673 ITGA2 208436 _ s _ at 3665 IRF7 227093 at 57602 USP36 208138 _ at 2520 GAST 200760 _ s _ at 10550 ARLÓIP5 20 241780 at 201790 _ s _ at 1717 DHCR7 200730 _ s _ at 7803 PTP4A1 1554980 a at 467 ATF3 219697 _ at 9956 HS3ST2 242255 at 22884 WDR37 201693 _ s _ at 1958 EGR1 219267 _ at 51228 GLTP 218847 _ at 10644 IGF2BP2 1555786 s at 645687 LINCO0520 230469 _ at 219790 RTKN2 229734 _ at 283174 LOC283174 209917 s at 11257 TP53TG1 242856 _ at 25 224329 _ s _ at 84518 CNFN 201037 _ at 5214 PFKP 212253 _ x _ at 100652766 / 1 /667 DST // / 1562970 at LOC100652766 201465 s at 3725 JUN 238058 _ at 150381 LOC150381 202067 _ s _ at 3949 LDLR 239334 _ at 57488 ESYT2 223679 _ at 1499 CTNNB1 222271 _ at 201235 _ s _ at 7832 BTG2 30 216718 _ at 388699 LINC00302 225662 _ at 51776 ZAK 219076 _ s _ at 5827 PXMP2 204401 at 3783 KCNN4 204475 _ at 4312 MMP1 222906 _ at 28982 FLVCR1 221185 _ s _ at 84223 IQCG 238613 _ at 51776 ZAK 203586 s at 379 ARLAD 206414 s at 8853 ASAP2 217802 _ s _ at 64710 NUCKS1 210794 _ s _ at 55384 MEG3 35 205767 at 2069 EREG 226621 _ at 9180 OSMR 228360 at 130576 LYPD6B 230682 _ x _ at 8714 ABCC3 228917 _ at 235668 at 639 PRDM1 228748 _ at 966 CD59 205483 _ s _ at 9636 ISG15 219632 _ s _ at 23729 / / / 7442 SHPK / I / TRPV1 215808 _ at 5655 KLK10 238715 at 646014 LOC646014 212281 _ s _ at 27346 TMEM97 218810 at 80149 ZC3H12A 212282 _ at 27346 TMEM97 225177 at 80223 RAB11FIP1 226287 at 91057 CCDC34 224454 _ at 55500 ETNK1 213618 _ at 116984 ARAP2 209498 at 634 CEACAM1 231089 _ at 100505664 LOC100505664 1557257 at 8915 BCL10 227140 at 3624 INHBA 225133 at 51274 KLF3 231467 _ at 202340 _ x _ at 3164 NR4A1 202967 _ at 2941 GSTA4 45 1556545 _ at 230323 _ s _ at 120224 TMEM45B 212474 _ at 23080 AVL9 224471 _ s _ at 8945 BTRC 210241 _ s _ at 11257 TP53TG1 202708 _ s _ at 8349 HIST2H2BE 243543 at 242871 at 54852 PAQR5 239132 at 4842 NOS1 205627 _ at 978 CDA 222757 _ s _ at 51776 ZAK 235542 _ at 200424 TET3 50 201194 _ at 6415 SEPW1 240410 _ at 229874 _ x _ at 100506687 LOC100506687 236656 _ s _ at 100288911 LOC100288911 202557 _ at 6782 HSPA13 206164 _ at 9635 CLCA2 239669 _ at 203159 _ at 2744 GLS 231907 _ at 27 ABL2 224991 _ at 80790 CMIP 229074 at 30844 EHD4 204258 _ at 1105 CHD1 55 205428 _ s _ at 794 CALB2 228249 _ at 119710 C1lorf74 205822 _ s _ at 3157 HMGCS1 229013 _ at 145783 LOC145783 210869 _ s _ at 4162 MCAM 211547 _ s _ at 5048 PAFAH1B1 225665 _ at 51776 ZAK 226863 _ at 642273 FAM110C 212781 _ at 5930 RBBP6 208161 _ s _ at 8714 ABCC3 232355 _ at 767579 SNORD114 - 3 214805 at 1973 EIF4A1 60 213288 _ at 129642 MBOAT2 229429 x _ at 728855 / 1 / 728875 LOC728855 / / / 221666 _ s _ at 29108 PYCARD LOC728875 203072 _ at 4643 MYO1E 202720 _ at 26136 TES 215465 at 26154 ABCA12 224995 _ at 56907 SPIRE1 224453 _ s _ at 55500 ETNK1 214771 _ x _ at 23164 MPRIP 216935 _ at 388699 LINC00302 201939 at 10769 PLK2 65 209086 _ x _ at 4162 MCAM 238587 _ at 84959 UBASHUB 218833 _ at 51776 ZAK US 10 ,378 ,059 B2 49 50 - continued - continued 209377 _ s _ at 9324 HMGN3 224595 _ at 23446 SLC44A1 223519 _ at 51776 ZAK 224613 _ s _ at 80331 DNAJC5 210138 _ at 8601 RGS20 212504 at 22982 DIP2C 1558845 _ at 100506089 LOC100506089 213682 _ at 10762 NUP50 201819 _ at 949 SCARB1 205247 _ at 4855 NOTCH4 204310 _ s _ at 4882 NPR2 228235 _ at 84848 MGC16121 239377 _ at 84285 EIF1AD 242873 _ at 224611 _ s _ at 80331 DNAJC5 205960 _ at 5166 PDK4 219155 _ at 26207 PITPNC1 230494 _ at 6574 SLC20A1 227163 _ at 119391 GSTO2 10 221260 _ s _ at 81566 CSRNP2 209633 _ at 5523 PPP2R3A 224480 _ s _ at 84803 AGPATO 219681 _ s _ at 80223 RAB11FIP1 210180 _ s _ at 6434 TRA2B 221860 _ at 3191 HNRNPL 204621 _ s _ at 4929 NR4A2 243296 _ at 10135 NAMPT 217863 _ at 8554 PIAS1 237133 _ at 236423 _ at 1556000 _ s _ at 55727 BTBD7 223421 _ at 50626 CYHR1 204681 _ s _ at 9771 RAPGEF5 220272 _ at 54796 BNC2 215726 s at 1528 CYB5A 201791 _ s _ at 1717 DHCR7 210886 _ x _ at 11257 TP53TG1 215574 _ at 226597 _ at 92840 REEP6 224328 _ s _ at 84648 LCE3D 204995 _ at 8851 CDK5R1 211828 _ s _ at 23043 TNIK 236119 _ s _ at 6706 SPRR2G 20 58367 _ s _ at 79744 ZNF419 219228 _ at 55422 ZNF331 218950 at 64411 ARAP3 234971 _ x _ at 113026 PLCD3 1552703 _ s _ at 114769 // / 834 CARD16 / I / CASP1 201127 _ s _ at 47 ACLY 219687 _ at 55733 HHAT 226880 _ at 64710 NUCKS1 232127 _ at 1184 CLCN5 209383 _ at 1649 DDIT3 218377 _ s _ at 10069 RWDD2B 204168 _ at 4258 MGST2 210335 _ at 9182 RASSF9 239670 _ at 65268 WNK2 25 227927 at 208512 _ s _ at 4301 MLLT4 227224 _ at 55103 RALGPS2 213281 at 3725 JUN 224778 s _ at 57551 TAOK1 218310 _ at 154881 / 1 / 27342 KCTD7 / / /RABGEF1 229566 _ at 645638 LOC645638 205151 s _ at 9865 TRIL 202734 _ at 9322 TRIP10 218217 at 59342 SCPEP1 201851 _ at 6455 SH3GL1 205055 _ at 3682 ITGAE 30 237337 _ at 215009 _ s _ at 100499177 THAP9 - AS1 37152 _ at 5467 PPARD 227484 _ at 57522 SRGAP1 209687 _ at 6387 CXCL12 239769 _ at 1009 CDH11 203152 at 64976 MRPL40 230360 _ at 342035 GLDN 201627 _ s _ at 3638 INSIG1 227112 _ at 23023 TMCC1 232593 _ at 93082 NEURL3 201482 _ at 5768 OSOX1 35 224769 _ at 57551 TAOK1 210337 _ s _ at 47 ACLY 209702 at 79068 FTO 203911 at 5909 RAPIGAP 204546 _ at 9764 KIAA0513 206683 _ at 7718 ZNF165 232224 _ at 5648 MASP1 202935 _ s _ at 6662 SOX9 239930 _ at 2590 GALNT2 218951 _ s _ at 55344 PLCXD1 203178 _ at 2628 GATM 233488 _ at 84659 RNASE7 40 235782 at 202562 _ s _ at 11161 C14orfi 218181 _ s _ at 9448 MAP4K4 208745 at 10632 ATP5L 233520 _ s _ at 202333 CMYA5 236078 _ at 57707 KIAA1609 213456 _ at 25928 SOSTDC1 226226 _ at 120224 TMEM45B 219528 _ s _ at 64919 BCL11B 213854 at 9145 SYNGR1 224945 at 55727 BTBD7 243955 _ at 214866 _ at 5329 PLAUR 222111_ at 54629 FAM63B 45 209941 at 8737 RIPK1 1560296 _ at 226029 _ at 57216 VANGL2 240038 _ at 212596 _ s _ at 10042 HMGXB4 211372 _ s _ at 7850 ILIR2 229873 _ at 283219 KCTD21 202672 _ s _ at 467 ATF3 226392 _ at 5922 RASA2 218717 _ s _ at 55214 LEPREL1 226005 _ at 7326 UBE2G1 228366 at 50 214445 at 22936 ELL2 230516 _ at 115416 MALSU1 227680 _ at 284695 ZNF326 201920 at 6574 SLC20A1 227786 _ at 90390 MED30 209632 _ at 5523 PPP2RJA 222067 _ x _ at 3017 HIST1H2BD 207367 _ at 479 ATP12A 1569106 _ s _ at 55209 SETD5 1557256 a at 231785 _ at 4909 NTF4 200811 _ at 1153 CIRBP 55 223937 _ at 27086 FOXP1 205201 _ at 2737 GLI3 1558685 _ a _ at 158960 LOC158960 227724 at 728190 LOC728190 211965 _ at 677 ZFP36L1 205403 _ at 7850 IL1R2 39549 _ at 4862 NPAS2 242827 _ x _ at 203800 _ s _ at 63931 MRPS14 228084 at 81579 PLA2G12A 1556321 _ a _ at — 209365 _ s _ at 1893 ECM1 60 212321 _ at 8879 SGPL1 243279 _ at 222154 _ s _ at 26010 SPATS2L 224946 s _ at 84317 CCDC115 218774 at 28960 DCPS 218708 _ at 29107 NXT1 212268 at 1992 SERPINB1 1560531_ at 353132 LCE1B 213134 _ x _ at 10950 BTG3 207761 s _ at 25840 METTL7A 230669 _ at 5922 RASA2 206011 _ at 834 CASP1 65 1559901 _ s _ at 388815 LINC00478 213703 _ at 150759 LINCO0342 225298 _ at 25953 PNKD US 10 , 378 , 059 B2 51 52 - continued -continued 242558 _ at 210993 _ s _ at 4086 SMAD1 226043 _ at 26086 GPSM1 238462 at 84959 UBASHUB 210236 _ at 8500 PPFIA1 211962 s at 677 ZFP36L1 214066 _ x _ at 4882 NPR2 224666 _ at 197370 NSMCE1 240024 _ at 23541 SEC14L2 239028 at 130574 LYPD6 235462 at 132864 CPEB2 213577 at 6713 SOLE 1554015 a at 1106 CHD2 202011 _ at 7082 TJP1 235347 _ at 84859 LRCH3 212254 s at 100652766 / 1/ 667 DST / // 230847 _ at 56897 WRNIP1 LOC100652766 201427 _ s _ at 6414 SEPP1 10 221701_ s _ at 64220 STRA6 1557905 s at 960 CD44 239576 _ at 57509 MTUS1 219084 _ at 64324 NSD1 234418 _ x _ at 960 CD44 206176 _ at 654 BMP6 227985 _ at 100506098 LOC100506098 219826 _ at 79744 ZNF419 213462 _ at 4862 NPAS2 212356 _ at 23351 KHNYN 224975 at 4774 NFIA 218909 _ at 26750 RPS6KC1 225990 at 91653 BOC 230555 _ s _ at 90390 MED30 240616 _ at 212687 _ at 3987 LIMS1 219911 _ s _ at 28231 SLCO4A1 203098 _ at 9425 CDYL 224970 _ at 4774 NFIA 229054 at 677 ZFP36L1 214623 _ at 26226 FBXW4P1 236039 _ at 284348 LYPD5 239478 _ x _ at 55668 C14orf118 209661 at 3801 KIFC3 20 226909 _ at 85460 ZNF518B 209560 _ s _ at 8788 DLK1 208670 _ s _ at 23741 EID1 225812 _ at 619208 C6orf225 206192 _ at 1041 CDSN 227829 _ at 120071 GYLTL1B 222173 _ s _ at 55357 TBC1D2 238623 _ at 228450 at 144100 PLEKHAZ 229415 _ at 54205 CYCS 1558097 _ at 253143 PRR14L 209222 _ s _ at 9885 OSBPL2 219373 _ at 54344 DPM3 1555809 _ at 83716 CRISPLD2 25 230388 _ s _ at 644246 KANSL1- AS1 204567 _ s _ at 9619 ABCG1 207098 _ s _ at 55669 MFN1 232277 _ at 64078 SLC28A3 223484 _ at 84419 C150rf48 237197 at 244804 at 8878 SQSTM1 225209 _ s _ at 118424 UBE2J2 229679 _ at 400073 C12orf76 231916 at 4842 NOS1 225826 _ at 326625 MMAB 212279 _ at 27346 TMEM97 30 213352 _ at 23023 TMCC1 204862 _ s _ at 4832 NME3 211883 _ x _ at 634 CEACAM1 230483 _ at 210387 _ at 8339 /1 / 8343 / / /8344 // / HIST1H2BC / / / 212856 _ at 23151 GRAMD4 8346 / / /8347 HIST1H2BE / / / 224650 _ at 114569 MAL2 HIST1H2BF / / / 202963 _ at 5993 RFX5 HIST1H2BG /I / 225320 _ at 90550 MCU 35 HIST1H2BI 236274 _ at 8662 EIF3B 210916 _ s _ at 960 CD44 209780 _ at 57157 PHTF2 221432 _ s _ at 81894 SLC25A28 218823 _ s _ at 54793 KCTD9 218487 _ at 210 ALAD 227787 _ s _ at 90390 MED30 223264 _ at 59274 MESDC1 230296 at 730094 C16orf52 206356 _ s _ at 2774 GNAL 222892 _ s _ at 55287 TMEM40 40 218097 _ s _ at 79004 CUEDC2 210610 _ at 634 CEACAM1 228001 _ at 757 TMEM5OB 230031 _ at 3309 HSPA5 212441 _ at 9778 KIAA0232 238477 _ at 10749 KIF1C 201854 s at 23300 ATMIN 209409 _ at 2887 GRB10 121 _ at 7849 PAX8 217995 at 58472 SQRDL 222143 _ s _ at 64419 MTMR14 226873 _ at 54629 FAM63B 1558002 _ at 11171 STRAP 1553722 _ s _ at 220441 RNF152 45 226040 _ at 204710 _ s _ at 26100 WIP12 226141 _ at 91050 CCDC149 212653 _ s _ at 23301 EHBP1 1556567 at 4676 NAP1L4 203979 _ at 1593 CYP27A1 226263_ at 154007 SNRNP48 244350 at 4651 MYO10 212074 at 23353 SUN1 223233 _ s _ at 57530 CGN 227387 _ at 54780 NSMCE4A 1555967 at 50 232795 at 214355 _ x _ at 100128553 / / / CTAGE15P / / / 203936 _ s _ at 4318 MMP9 100142659 / 1 / 340307 / / / CTAGE4 / / / 225033 _ at 6482 ST3GAL1 441294 / 1 /643854 CTAGE6P / / / 209109 _ s _ at 7105 TSPAN6 CTAGES / I /CTAGES 213351 _ s _ at 23023 TMCC1 214469 _ at 3012 /1 / 8335 HIST1H2AB / / / 203047 _ at 6793 STK10 HIST1H2AE 55 220721 at 80110 ZNF614 212472 _ at 9645 MICAL2 1556127 _ at 23181 DIP2A 228115 _ at 64762 FAM59A 215016 _ x _ at 100652766 // /667 DST / / / 228964 _ at 639 PRDM1 LOC100652766 230027 _ s _ at 84545 MRPL43 206576 _ s _ at 634 CEACAM1 207318 _ s _ at 8621 CDK13 240674 at 3720 JARID2 221689 _ s _ at 51227 PIGP 60 225646 at 1075 CTSC 219270 _ at 79094 CHAC1 1554010 _ at 3340 NDST1 225299 _ at 4645 MYO5B 204100 _ at 7067 THRA 239770 _ at 83850 ESYT3 221840 _ at 5791 PTPRE 226399 _ at 79982 DNAJB14 209078 _ s _ at 25828 TXN2 226656 at 10491 CRTAP 218530 at 29109 FHOD1 228852 _ at 2029 ENSA 65 235434 _ at 206239 _ s _ at 6690 SPINK1 230063 _ at 9422 ZNF264 US 10 , 378 , 059 B2 53 54 -continued - continued 40420 at 6793 STK10 208490 _ x _ at 8339 / 1 /8343 / / / 8344 / / / HIST1H2BC / I / 221027 _ s _ at 81579 PLA2G12A 8346 / / /8347 HIST1H2BE / / / 244202 at HIST1H2BF / / / 212108 _ at 23197 FAF2 HIST1H2BG / / / 204294 _ at 275 AMT HIST1H2BI 225503 _ at 207063 DHRSX 235514 _ at 151516 ASPRV1 212810 _ s _ at 6509 SLC1A4 209098 _ s _ at 182 JAG1 214814 _ at 91746 YTHDC1 1554229 at 153222 CREBRF 228468 _ at 84930 MASTL 209398 _ at 3006 HISTIHIC 209108 _ at 7105 TSPAN6 10 202629 at 10513 APPBP2 220444 _ at 79230 ZNF557 203428 _ s _ at 25842 ASF1A 206172 _ at 3598 IL13RA2 238005 _ s _ at 25942 SIN3A 225002 _ s _ at 25870 SUMF2 214455 at 8339 / 1 /8343 / / / 8344 / / / HIST1H2BC / II 212205 _ at 94239 H2AFV 8346 / // 8347 HIST1H2BE / / / 228851 s at 2029 ENSA HIST1H2BF / / / 209048 _ s _ at 23613 ZMYNDS HIST1H2BG / / / 211846 _ s _ at 5818 PVRL1 HIST1H2BI 238909 _ at 6281 S100A10 214073 _ at 2017 CTTN 205503 at 5784 PTPN14 203140 _ at 604 BCL6 243829 _ at 673 BRAF 232150 _ at 244379 _ at 208546 _ x _ at 8345 HIST1H2BH 223251 _ s _ at 55608 ANKRD10 20 243446 at 84962 AJUBA 202633 _ at 11073 TOPBP1 236207 at 6744 SSFA2 214502 at 8970 HIST1H2BJ 212016 _ s _ at 5725 PTBP1 221773 _ at 2004 ELK3 232311 at 567 B2M 41858 _ at 27315 PGAP2 219711 at 54807 ZNF586 212850 s _ at 4038 LRP4 208579 _ x _ at 54145 / / / 85236 H2BFS /I / 223408 s at HIST1H2BK 214472 _ at 3013 / / / 8350 / / /8351 // / HIST1H2AD /I / 25 239493 at 6129 RPL7 8352 / 1 /8353 / 1 / 8354 / // HIST1HGAJI ! 214074 _ s _ at 2017 CTTN 8355 / / / 8356 / 1 /8357 HIST1H3B / / / 228091 at 55014 STX17 8358 / HIST1H3C / / / 234331 _ s _ at 151354 FAM84A HIST1H3D / I / 212372 _ at 4628 MYH10 HIST1H3E / // HIST1H3F / / / 30 Probeset ID Gene Title HIST1H3G // / HIST1H3H // / 222450 _ at prostate transmembrane HIST1H31/ / / protein , androgen induced 1 HIST1H3J 233565 _ s_ at FKBP1A - SDCBP2 readthrough 225647 _ s _ at 1075 CTSC (non - protein coding) / // 1559977 _ a _ at 284723 SLC25A34 35 syndecan binding protein 211347 _ at 8555 CDC14B (syntenin ) 1558208 _ at 242832 _ at period homolog 1 ( Drosophila) 227570 _ at 144110 TMEM86A 240463 _ at 227492 at 100506658 / 1 /647859 LOC647859 / / /OCLN 213039 _ at Rho/ Rac guanine nucleotide 1558778 s at 57496 MKL2 exchange factor (GEF ) 18 31637 _ s _ at 7067 / / /9572 NR1D1 / / / THRA 40 235072 s _ at kinesin family member 13A 229190 _ at 100507376 LOC100507376 208926 at sialidase 1 ( lysosomal 236188 _ s _ at 4676 NAP1L4 sialidase ) 212503 _ s _ at 22982 DIP2C 237444 _ at 204760 _ s _ at 7067 / 1 / 9572 NR1D1 / / / THRA 239451 _ at 212099 at 388 RHOB 222288 at 214873 _ at 91355 LRP5L 227579 _ at fer (fps / fes related ) tyrosine 45 kinase 228181 _ at 7779 SLC30A1 212717 _at pleckstrin homology domain 212763 _ at 23271 CAMSAP2 containing , family M ( with RUN 226285 _ at 4076 CAPRIN1 domain ) member 1 213567 _ at 3840 K???4 226853 _ at BMP2 inducible kinase 203927 _ at 4794 NFKBIE 214112 _ s _ at chromosome X open reading 208523 x at 8339/ 1 / 8343 // / 8344 // / HIST1H2BC / II 50 frame 40A / / /chromosome X 8346 / / / 8347 HIST1H2BE / / / open reading frame 40B HIST1H2BF / / / 209012 _ at triple functional domain (PTPRF HIST1H2BG / // interacting) HIST1H2BI 219476 _ at chromosome 1 open reading 219389 _ at 55061 SUSD4 frame 116 202329 _ at 1445 CSK 55 238086 _ at uncharacterized 238523 _ at 79786 KLHL36 LOC100129617 1565016 _ at 3276 PRMT1 230721 _ at chromosome 16 open reading 226409 _ at 128637 TBC1D20 frame 52 229926 _ at 100500850 MIR3682 1566079 _ at ribosomal protein S16 208527 _ x _ at 8339 / 1 / 8343 / / /8344 / / / HIST1H2BC / II pseudogene 5 8346 /1 / 8347 HIST1H2BE / II 60 223839 _ s _ at stearoyl- CoA desaturase (delta HIST1H2BF / / / 9 - desaturase ) HIST1H2BG / / / 225671 _ at spinster homolog 2 (Drosophila ) HIST1H2BI 212961_ x _ at chromosome X open reading 223598 _ at 5887 RAD23B frame 40B 243797 _ at 9262 STK17B 223659 at transmembrane protease , 203317 _ at 23550 PSD4 65 serine 13 230965 _ at 9099 USP2 229909 _ at beta - 1 , 4 - N - acetyl- galactosaminyl US 10 , 378 ,059 B2 55 56 - continued - continued 223467 _ at transferase 3 RAS , dexamethasone 203159 at glutaminase induced 1 224991 at C -Maf inducing protein 235146 _ at transmembrane and coiled - coil 204258 _ at chromodomain helicase DNA domain family 3 binding protein 1 235548 _ at adenomatosis polyposis coli 228249 _ at chromosome 11 open reading down- regulated 1 - like frame 74 206816 _ s _ at sperm associated antigen 8 229013 _ at uncharacterized LOC145783 242323 at phospholipase A2 , group XIIA platelet -activating factor 224579 at solute carrier family 38 , 211547 _ s _ at acetylhydrolase lb , regulatory member 1 10 subunit 1 (45kDa ) 213315 _ x _ at chromosome X open reading 226863 _ at family with sequence similarity frame 40A 110 , member C 227314 _ at integrin , alpha 2 (CD49B , alpha 208161 _ s _ at ATP -binding cassette , sub 2 subunit of VLA - 2 receptor) family C ( CFTR /MRP ) , member 3 227093 _ at Ubiquitin specific peptidase 36 214805 _ at eukaryotic translation initiation 200760 _ s _ at ADP - ribosylation - like factor 6 factor 4A1 interacting protein 5 229429 _ x _ at uncharacterized LOC728855 // / 201790 _ s _ at 7 -dehydrocholesterol reductase uncharacterized LOC728875 1554980 _ a _ at activating transcription factor 3 202720 _ at testis derived transcript ( 3 LIM 242255 at WD repeat domain 37 domains ) 219267 _ at glycolipid transfer protein 224995 _ at spire homolog 1 (Drosophila ) 1555786 s at long intergenic non -protein 214771 _ x _ at myosin phosphatase Rho coding RNA 520 20 interacting protein 229734 _ at uncharacterized LOC283174 201939 _ at polo - like kinase 2 242856 _ at 238587 _ at ubiquitin associated and SH3 201037 _ at phosphofructokinase, platelet domain containing B 1562970 at 232113 at 201465 _ s _ at jun proto -oncogene 208690 s at PDZ and LIM domain 1 202067 _ s _ at low density lipoprotein receptor 25 201464 _ x _ at jun proto - oncogene 223679 _ at catenin ( cadherin -associated 236657 _ at uncharacterized protein ), beta 1 , 88kDa LOC100288911 201235 _ s _ at BTG family, member 2 215541 _ s _ at diaphanous homolog 1 225662 _ at sterile alpha motif and leucine (Drosophila ) zipper containing kinase AZK 238028 at chromosome 6 open reading potassium intermediate / small 30 frame 132 204401 at conductance calcium - activated 226893 _ at V -abl Abelson murine leukemia channel, subfamily N , member viral oncogene homolog 2 222906 _ at feline leukemia virus subgroup 237576 _ x _ at uncharacterized C cellular receptor 1 LOC100506480 238613 at sterile alpha motif and leucine 1552256 _ a _ at scavenger receptor class B , zipper containing kinase AZK 35 member 1 ArfGAP with SH3 domain , 215255 _ at immunoglobulin superfamily , 206414 _ s _ at ankyrin repeat and PH domain member 9B 2 1557258 _ a _ at B - cell CLL / lymphoma 10 210794 _ s _ at maternally expressed 3 (non -protein 240623 _ at coding ) solute carrier family 6 226621 _ at oncostatin M receptor 40 228754 at (neurotransmitter transporter , 230682 _ x _ at ATP - binding cassette , sub - family C taurine ) , member 6 (CFTR MRP/ ) , member3 217257 _ at SH3 - domain binding protein 2 235668 _ at PR domain containing 1 , with 241036 at ZNF domain 242553 _ at ATP -binding cassette , sub 205483 _ s _ at ISG15 ubiquitin - like modifier family C (CFTR /MRP ) , member 3 215808 _ at kallikrein - related peptidase 10 45 239358 _ at 212281 _ s _ at transmembrane protein 97 210868 _ s _ at ELOVL fatty acid elongase 6 212282 _ at transmembrane protein 97 platelet- activating factor 226287 _ at coiled - coil domain containing 34 213618 _ at ArfGAP with RhoGAP domain , 200815 _ s _ at acetylhydrolase lb , regulatory ankyrin repeat and PH domain subunit 1 (45kDa ) 2 208436 s at interferon regulatory factor 7 231089 _at uncharacterized 50 208138 _ at gastrin LOC100505664 241780 at 227140 _ at inhibin , beta A 200730 _ s _ at protein tyrosine phosphatase 231467 _ at type IVA , member 1 202967 _ at glutathione S -transferase alpha 219697 _ at heparan sulfate ( glucosamine ) 3 - 0 -sulfotransferase 2 230323 _ s _ at transmembrane protein 45B 55 201693 _ s _ at early growth response 1 224471 _ s _ at beta - transducin repeat 218847 _ at insulin - like growth factor 2 containing E3 ubiquitin protein mRNA binding protein 2 ligase 230469 _ at rhotekin 2 202708 s at histone cluster 2 , H2be 209917 _ s _ at TP53 target 1 (non -protein 242871 _ at progestin and adipoQ receptor coding ) family member V 60 224329 _ s _ at cornifelin 205627 _ at cytidine deaminase 212253 _ x _ at dystonin /l /dystonin - like 235542 _ at tet methylcytosine dioxygenase 238058 at uncharacterized LOC150381 239334 _ at Extended synaptotagmin - like 240410 at protein 2 236656 _ s _ at uncharacterized 222271 at LOC100288911 65 216718 at long intergenic non -protein 206164 _ at chloride channel accessory 2 coding RNA 302 US 10 , 378 ,059 B2 57 58 - continued - continued 219076 s at peroxisomal membrane protein 210138 _ at regulator of G -protein signaling 2 , 22kDa 20 204475 _ at matrix metallopeptidase 1 1558845 _ at uncharacterized ( interstitial collagenase ) LOC100506089 221185 _ s _ at IQ motif containing G 201819 _ at scavenger receptor class B , 203586 _ s _ at ADP - ribosylation factor - like 4D member 1 nuclear casein kinase and 204310 _ s _ at natriuretic peptide receptor 217802 _ s _ at cyclin - dependent kinase B / guanylate cyclase B substrate 1 (atrionatriuretic peptide 205767 at epiregulin 10 receptor B 228360 _ at LY6 /PLAUR domain containing 239377 at eukaryotic translation initiation 6B factor 1A domain containing 228917 _ at 224611 _ s _ at DnaJ (Hsp40 ) homolog , 228748 _ at CD59 molecule , complement subfamily C , member 5 regulatory protein 219155 _ at phosphatidylinositol transfer 219632 _ s _ at sedoheptulokinase /l / transient protein , cytoplasmic 1 receptor potential cation 227163 _ at glutathione S -transferase channel, subfamily V , member omega 2 238715 _ at Uncharacterized LOC646014 209633 _ at protein phosphatase 2 , 218810 _ at zinc finger CCCH - type regulatory subunit B " , alpha containing 12A 219681_ s _ at RAB11 family interacting 225177 _ at RAB11 family interacting protein 1 (class I ) protein 1 ( class I) 20 221860 _ at heterogeneous nuclear 224454 at ethanolamine kinase 1 ribonucleoprotein L 209498 _ at carcinoembryonic antigen 243296 _ at Nicotinamide related cell adhesion molecule phosphoribosyltransferase 1 (biliary glycoprotein ) 237133 _ at 1557257 at B - cell CLL / lymphoma 10 1556000 s _ at BTB ( POZ ) domain containing 7 225133 _ at Kruppel - like factor 3 (basic ) 25 204681 _ s _ at Rap guanine nucleotide 202340 _ x _ at nuclear receptor subfamily 4 , exchange factor (GEF ) 5 group A , member 1 215726 _ s _ at cytochrome b5 type A 1556545 _ at (microsomal ) 212474 _ at AVL9 homolog ( S . cerevisiase ) 210886 _ x _ at TP53 target 1 (non -protein 210241 _ s _ at TP53 target 1 (non - protein coding ) coding ) 30 226597 at receptor accessory protein 6 243543 _ at 204995 at cyclin - dependent kinase 5 , 239132 _ at nitric oxide synthase 1 regulatory subunit 1 (p35 ) ( neur 236119 _ s _ at small proline- rich protein 2G 222757 _ s _ at sterile alpha motif and leucine 219228 at zinc finger protein 331 zipper containing kinase AZK 234971 _ x _ at phospholipase C , delta 3 201194 at selenoprotein W , 1 35 201127 _ s _ at ATP citrate lyase 229874 _ x _ at uncharacterized 226880 at Nuclear casein kinase and LOC100506687 cyclin - dependent kinase 202557 _ at heat shock protein 70kDa substrate 1 family , member 13 209383 _ at DNA - damage - inducible 239669 _ at - trans 231907 _ at v -abl Abelson murine leukemia 40 204168 _ at microsomal glutathione S viral oncogene homolog 2 transferase 2 229074 _ at EH -domain containing 4 239670 _ at WNK lysine deficient protein 205428 s at calbindin 2 kinase 2 205822 _ s _ at 3 - hydroxy - 3 -methylglutaryl - CoA 208512 _ s _ at myeloid /lymphoid or mixed synthase 1 ( soluble ) lineage leukemia (trithorax homolog , 210869 _ s _ at melanoma cell adhesion Drosophila ); translocate 45 213281 at Jun proto -oncogene molecule 218310 _ at potassium channel 225665 _ at sterile alpha motif and leucine tetramerisation domain zipper containing kinase AZK containing 7 / / I RAB guanine 212781 _ at retinoblastoma binding protein nucleotide exchan 205151 _ s _ at TLR4 interactor with leucine - rich 232355 _ at small nucleolar RNA , C /D box 50 repeats 114 - 3 218217 _ at serine carboxypeptidase 1 213288 _ at membrane bound ( - acyltransferase 205055 _ at integrin , alpha E (antigen domain containing 2 CD103 , human mucosal 221666 _ s _ at PYD and CARD domain lymphocyte antigen 1 ; alpha containing polypeptide 203072 _ at myosin IE 55 215009 _ s _ at THAP9 antisense RNA 1 (non 215465 _ at ATP - binding cassette , sub- family A protein coding) ( ABC1 ) , member 12 227484 _ at SLIT -ROBO Rho GTPase 224453 _ s _ at ethanolamine kinase 1 activating protein 1 216935 _ at long intergenic non -protein 239769 _ at Cadherin 11 , type 2 , OB - cadherin coding RNA 302 230360 _ at (osteoblast ) gliomedin 209086 _ x _ at melanoma cell adhesion 60 227112 at transmembrane and coiled -coil molecule domain family 1 218833 _at sterile alpha motif and leucine 201482 _ at quiescin 06 sulfhydryl oxidase zipper containing kinase AZK 209377 _ s _ at high mobility group 210337 _ s _ at ATP citrate lyase nucleosomal binding domain 3 203911 at RAP1 GTPase activating 223519 _ at sterile alpha motif and leucine 65 protein zipper containing kinase AZK 206683 _ at zinc finger protein 165 US 10 , 378 ,059 B2 59 60 - continued - continued 202935 _ s _ at SRY ( sex determining region 220272 _ at basonuclin 2 Y ) -box 9 201791 _ s _ at 7 -dehydrocholesterol reductase 218951 _ s _ at phosphatidylinositol- specific 215574 at phospholipase C , X domain 224328 _ s _ at late cornified envelope 3D containing 1 211828 _ s _ at TRAF2 and NCK interacting 233488 _ at ribonuclease, RNase A family , 7 kinase 202562 _ s _ at chromosome 14 open reading 58367 _ s _ at zinc finger protein 419 frame 1 218950 _ at ArfGAP with RhoGAP domain , 208745 _ at ATP synthase , H + transporting , ankyrin repeat and PH domain mitochondrial Fo complex , 10 subunit G 1552703 _ s _ at caspase recruitment domain 236078 _ at KIAA1609 family , member 16 / // caspase 226226 _ at transmembrane protein 45B 1 , apoptosis -related cysteine 213854 _ at synaptogyrin 1 219687 _ at hedgehog acyltransferase 243955 _ at 232127 _ at chloride channel , voltage -sensitive 5 222111 _ at family with sequence similarity 218377 _ s _ at RWD domain containing 2B 63, member B 210335 _ at Ras association ( RaIGDS /AF - 6 ) 1560296 _ at domain family ( N - terminal ) 240038 _ at member 9 211372 _ s _ at interleukin 1 receptor, type II 227927 _ at 202672 _ s _ at activating transcription factor 3 227224 at Ral GEF with PH domain and 218717 _ s _ at leprecan - like 1 20 SH3 binding motif 2 228366 _ at 224778 _ s _ at TAO kinase 1 230516 _ at Mitochondrial assembly of 229566 _ at WDNM1- like pseudogene ribosomal large subunit 1 202734 _ at thyroid hormone receptor 201920 _ at solute carrier family 20 interactor 10 (phosphate transporter ) , 201851 _ at SH3- domain GRB2 - like 1 member 1 237337 _ at 209632 _ at protein phosphatase 2 , 25 37152 at peroxisome proliferator - activated receptor regulatory subunit B " , alpha delta 207367 _ at ATPase , H + / K + transporting, 209687 _ at chemokine ( C - X - C motif ) ligand 12 nongastric , alpha polypeptide 203152 _ at mitochondrial ribosomal protein 1557256 a at L40 200811 _ at cold inducible RNA binding 201627 _ s _ at insulin induced gene 1 protein 30 232593 at neuralized homolog 3 205201 _ at GLI family zinc finger 3 (Drosophila ) pseudogene 227724 _ at uncharacterized LOC0728190 224769 _ at TAO kinase 1 205403 _ at interleukin 1 receptor, type II 209702 _ at fat mass and obesity associated 242827 _ x _ at - 204546 at KIAA0513 228084 _ at phospholipase A2, group XIIA 232224 at mannan - binding lectin serine 209365 _ s _ at extracellular matrix protein 1 35 peptidase 1 ( C4 / C2 activating 243279 _ at — component of Ra - reactive fac 224946 s at coiled - coil domain containing 239930 at UDP - N - acetyl- alpha - D - galactosamine : 115 polypeptide N - acetylgalactosaminyl 218708 _ at NTF2 - like export factor 1 transferase 2 (Gal 1560531 _ at late cornified envelope 1B 203178 _ at glycine amidinotransferase ( L - arginine: 207761 _ s _ at methyltransferase like 7A 40 glycine amidinotransferase ) 206011 _ at caspase 1 , apoptosis -related 235782 at cysteine peptidase 218181_ s _ at mitogen -activated protein 213703 _ at long intergenic non -protein kinase kinase kinase kinase 4 coding RNA 342 233520 _ s _ at cardiomyopathy associated 5 224595 _ at solute carrier family 44 , 213456 _ at sclerostin domain containing 1 member 1 219528 s at B -cell CLL /lymphoma 11B ( zinc 224613 _ s _ at DnaJ (Hsp40 ) homolog , 45 finger protein ) subfamily C , member 5 212504 _ at DIP2 disco - interacting protein 2 224945 _ at BTB ( POZ ) domain containing 7 homolog C (Drosophila ) 214866 _ at plasminogen activator, 213682 _ at nucleoporin 50kDa urokinase receptor 205247 _ at notch 4 209941 _ at receptor ( TNFRSF )- interacting 228235 _ at uncharacterized protein 50 serine - threonine kinase 1 MGC16121 226029 at yang - like 2 ( van gogh , 242873 _ at Drosophila ) 205960 _ at pyruvate dehydrogenase 212596 _ s _ at HMG box domain containing 4 kinase , isozyme 4 229873 at potassium channel 230494 at solute carrier family 20 tetramerisation domain ( phosphate transporter) , 55 containing 21 member 1 226392 _ at RAS p21 protein activator 2 221260 _ s _ at cysteine -serine -rich nuclear 226005 _ at ubiquitin -conjugating enzyme protein 2 E2G 1 224480 _ s _ at 1 -acylglycerol - 3 -phosphate 0 214445 _ at elongation factor, RNA acyltransferase 9 polymerase II, 2 210180 _ s _ at transformer 2 beta homolog 60 227680 _ at zinc finger protein 326 (Drosophila ) 227786 at mediator complex subunit 30 204621 _ s _ at nuclear receptor subfamily 4 , 222067 _ x _ at histone cluster 1 , H2bd group A , member 2 1569106 _ s _ at SET domain containing 5 217863 _ at protein inhibitor of activated 231785 _ at neurotrophin 4 STAT, 1 223937 _ at forkhead box P1 236423 _ at 65 1558685 _ a _ at uncharacterized protein 223421 _ at cysteine/ histidine - rich 1 BC009467 US 10 , 378 , 059 B2 61 62 - continued - continued 211965 _ at zinc finger protein 36 , C3H 204862 _ s _ at NME/ NM23 nucleoside type -like 1 diphosphate kinase 3 39549 _ at neuronal PAS domain protein 2 230483 _ at 203800 _ s _ at mitochondrial ribosomal protein 212856 at GRAM domain containing 4 S14 224650 _ at mal, T - cell differentiation protein 1556321 _ a at 2 (gene / pseudogene ) 212321 at sphingosine - 1 -phosphate lyase 202963 _ at regulatory factor X , 5 ( influences HLA class II 222154 s _ at spermatogenesis associated , expression ) serine -rich 2 - like 10 225320 at mitochondrial calcium uniporter 218774 _ at decapping enzyme, scavenger 236274 at eukaryotic translation initiation 212268 _ at serpin peptidase inhibitor, clade factor 3 , subunit B B (ovalbumin ) , member 1 209780 _ at putative homeodomain 213134 _ x _ at BTG family , member 3 transcription factor 2 230669 _ at RAS p21 protein activator 2 potassium channel 1559901_ s _ at long intergenic non -protein 218823 _ s _ at tetramerisation domain coding RNA 478 containing 9 225298 _ at paroxysmal nonkinesigenic 227787 _ s _ at mediator complex subunit 30 dyskinesia 230296 _ at chromosome 16 open reading 242558 _ at frame 52 226043 _ at G -protein signaling modulator 1 222892 _ s _ at transmembrane protein 40 210236 _ at protein tyrosine phosphatase , 210610 _ at carcinoembryonic antigen -related receptor type , f polypeptide 20 cell adhesion moleculel (biliary ( PTPRF ) , interacting protein glycoprotein ) 214066 _ x _ at natriuretic peptide receptor 230031 _ at heat shock 70kDa protein 5 B / guanylate cyclase B ( glucose -regulated protein , ( atrionatriuretic peptide receptor 78kDa ) B 238477 at kinesin family member 10 240024 _ at SEC14 - like 2 ( S . cerevisiae ) 25 209409 _ at growth factor receptor -bound 235462 _ at Cytoplasmic polyadenylation protein 10 element binding protein 2 217995 _ at sulfide quinone reductase - like 1554015 _ a _ at chromodomain helicase DNA ( yeast ) binding protein 2 226873 _ at family with sequence similarity 235347 _ at leucine - rich repeats and 63 , member B calponin homology (CH ) 30 1553722 _ s _ at ring finger protein 152 domain containing 3 204710 _ s _ at WD repeat domain , 230847 _ at Werner helicase interacting phosphoinositide interacting 2 protein 1 212653 _ s _ at EH domain binding protein 1 201427 _ s _ at selenoprotein P , plasma , 1 203979 at cytochrome P450 , family 27 , 1557905 _ s _ at CD44 molecule (Indian blood subfamily A , polypeptide 1 group ) 35 244350 _ at myosin X 219084 _ at nuclear receptor binding SET 223233 _ s _ at cingulin domain protein 1 1555967 at — 206176 _ at bone morphogenetic protein 6 214355 _ x _ at CTAGE family , member 15 , 219826 _ at zinc finger protein 419 pseudogenel // CTAGE family , 212356 at KH and NYN domain containing member 4 / // CTAGE family , 218909 _ at ribosomal protein S6 kinase , member 52kDa , polypeptide 1 40 214469 _ at histone cluster 1 , H2ab // / 230555 _ s _ at Mediator complex subunit 30 histone cluster 1 , H2ae 212687 _ at LIM and senescent cell antigen 212472 _ at microtubule associated like domains 1 monoxygenase , calponin and LIM domain containing 2 203098 at chromodomain protein , Y - like family with sequence similarity 229054 at zinc finger protein 36 , C3H 45 228115 _ at type - like 1 59 , member A 228964 at PR domain containing 1 , with 236039 _ at LY6 /PLAUR domain containing ZNF domain 230027 _ s _ at mitochondrial ribosomal protein 209661 _ at kinesin family member C3 L43 209560 _ s _ at delta - like 1 homolog 207318 _ s _ at cyclin - dependent kinase 13 (Drosophila ) 50 221689 _ s _ at phosphatidylinositol glycan 225812 _ at chromosome 6 open reading anchor biosynthesis , class P frame 225 219270 _ at ChaC , cation transport regulator 227829 _ at glycosyltransferase- like 1B homolog 1 ( E . coli ) 238623 _ at 225299 _ at myosin VB 229415 _ at cytochrome c , somatic 239770 at extended synaptotagmin - like 209222 _ s _ at oxysterol binding protein - like 2 55 protein 3 1555809 _ at cysteine -rich secretory protein 226399 _ at DnaJ (Hsp40 ) homolog , LCCL domain containing 2 subfamily B , member 14 204567 _ s _ at ATP -binding cassette , sub - family 226656 _ at cartilage associated protein G (WHITE ) , member 1 228852 _ at endosulfine alpha 232277 _ at solute carrier family 28 ( sodium 206239 _ s _ at serine peptidase inhibitor, Kazal coupled nucleoside 60 type 1 transporter ), member 3 210993 _ s _ at SMAD family member 1 237197 _ at 238462 _ at ubiquitin associated and SH3 225209 _ s _ at ubiquitin - conjugating enzyme domain containing B E2 , J2 211962 _ s _ at zinc finger protein 36 , C3H 231916 _ at nitric oxide synthase 1 type- like 1 ( neuronal ) 65 224666 at non - SMC element 1 homolog 212279 _ at transmembrane protein 97 ( S . cerevisiae ) US 10 , 378 ,059 B2 63 64 - continued - continued 239028 _ at LY6 /PLAUR domain containing 226263 _ at small nuclear ribonucleoprotein 48kDa (U11 / U12 ) 213577 _ at squalene epoxidase 212074 at Sad1 and UNC84 domain 202011 _ at tight junction protein 1 ( zona containing 1 occludens 1 ) 227387 _ at Non - SMC element 4 homolog A 212254 sat dystonin / /dystonin - like ( S . cerevisiae ) 221701 _ s _ at stimulated by retinoic acid gene 232795 _ at 6 homolog (mouse ) 203936 s at matrix metallopeptidase 9 239576 _ at microtubule associated tumor (gelatinase B , 92kDa suppressor 1 10 gelatinase , 92kDa type IV 234418 _ x _ at CD44 molecule ( Indian blood collagenase ) group ) 225033 at ST3 beta -galactoside alpha - 2 , 3 227985 _ at uncharacterized sialyltransferase 1 LOC100506098 209109 _ s _ at tetraspanin 6 213462 _ at neuronal PAS domain protein 2 213351 _ s _ at transmembrane and coiled - coil 224975 _ at nuclear factor I/ A 15 domain family 1 225990 _ at Boc homolog (mouse ) 203047 _ at serine / threonine kinase 10 240616 at 220721 at zinc finger protein 614 219911 _ s _ at solute carrier organic anion 1556127 at DIP2 disco - interacting protein 2 transporter family , member 4A1 homolog A (Drosophila ) 224970 at nuclear factor I/ A 215016 _ x _ at dystonin /l /dystonin - like 214623 _ at F -box and WD repeat domain 20 206576 s at carcinoembryonic antigen -related containing 4 pseudogene 1 cell adhesion molecule 239478 _ x _ at chromosome 14 open reading 1 (biliary glycoprotein ) frame 118 240674 _ at jumonji , AT rich interactive 226909 _ at zinc finger protein 518B domain 2 208670 _ s _ at EP300 interacting inhibitor of 225646 _ at cathepsin C differentiation 1 1554010 _ at N - deacetylase / N - sulfotransferase 206192 _ at corneodesmosin 25 (heparan glucosaminyl ) 1 222173 _ s _ at TBC1 domain family , member 2 204100 _ at thyroid hormone receptor, alpha 228450 _ at pleckstrin homology domain 221840 _ at protein tyrosine phosphatase , containing, family A member 7 receptor type , E 1558097 _ at proline rich 14 - like 209078 _ s _ at thioredoxin 2 219373 at dolichyl -phosphate 218530 _ at formin homology 2 domain mannosyltransferase 30 containing 1 polypeptide 3 235434 _ at 230388 s at KANSL1 antisense RNA 1 (non 230063 _ at zinc finger protein 264 protein coding) 40420 _ at serine / threonine kinase 10 207098 _ s _ at mitofusin 1 221027 _ s _ at phospholipase A2 , group XIIA 223484 _ at chromosome 15 open reading 244202 at frame 48 35 212108 _ at Fas associated factor family 244804 _ at sequestosome 1 member 2 229679 _ at chromosome 12 open reading 204294 _ at aminomethyltransferase frame 76 225503 _ at dehydrogenase / reductase 225826 at methylmalonic aciduria ( SDR family ) X - linked (cobalamin deficiency ) cbIB 212810 _ s _ at solute carrier family 1 type 40 ( glutamate /neutral amino acid 213352 _ at transmembrane and coiled - coil transporter) , member 4 domain family 1 214814 _ at YTH domain containing 1 211883 _ x _ at carcinoembryonic antigen - related 228468 _ at microtubule associated cell adhesion molecule 1 (biliary serine/ threonine kinase - like glycoprotein ) 209108 at tetraspanin 6 210387 _ at histone cluster 1 , H2bc / // 220444 _ at zinc finger protein 557 histone cluster 1 , H2be // / 45 206172 _ at interleukin 13 receptor , alpha 2 histone cluster 1 , H2bf/ / /his 225002 _ s _ at sulfatase modifying factor 2 210916 _ s _ at CD44 molecule ( Indian blood 212205 _ at H2A histone family, member V group ) 228851 _ s _ at endosulfine alpha 221432 _ s _ at solute carrier family 25 209048 _ s _ at zinc finger, MYND - type (mitochondrial iron transporter ), containing 8 member 28 50 211846 _ s _ at poliovirus receptor -related 1 218487 _ at aminolevulinate dehydratase ( herpesvirus entry mediator C ) 223264 _ at mesoderm development 238909 _ at S100 calcium binding protein candidate 1 A10 206356 _ s _ at guanine nucleotide binding 205503 _ at protein tyrosine phosphatase , protein ( G protein ) , alpha non -receptor type 14 activating activity polypeptide , 55 243829 _ at V -raf murine sarcoma viral 218097 _ s _ at CUE domain containing 2 oncogene homolog B1 228001 _ at transmembrane protein 50B 244379 at 212441 _ at KIAA0232 223251 _ s _ at ankyrin repeat domain 10 201854 _ s _ at ATM interactor 202633 _ at topoisomerase (DNA ) II binding 121 _ at paired box 8 protein 1 222143 _ s _ at myotubularin related protein 14 60 214502 _ at histone cluster 1 , H2bj 1558002 _ at Serine/ threonine kinase 221773 at ELK3 , ETS -domain protein receptor associated protein ( SRF accessory protein 2 ) 226040 _ at 41858 _ at post -GPI attachment to proteins 226141 at coiled -coil domain containing 149 212850 _ s _ at low density lipoprotein receptor 1556567 at nucleosome assembly protein 65 related protein 4 1 - like 4 223408 _ s _ at US 10 ,378 ,059 B2 65 66 - continued -continued 214472 _ at histone cluster 1 , H2ad // / 232150 _ at histone cluster 1 , H3a/ / / 208546 _ x _ at histone cluster 1 , H2bh histone cluster 1 , H3b / // histo 243446 _ at ajuba LIM protein 225647 _ s _ at cathepsin C 1559977 _ a _ at solute carrier family 25 , 236207 _ at sperm specific antigen 2 member 34 212016 _ s _ at polypyrimidine tract binding 211347 _ at CDC14 protein 1 homolog B (S . cerevisiae) 232311 _ at Beta - 2 -microglobulin 1558208 _ at 219711 _ at zinc finger protein 586 227570 _ at transmembrane protein 86A 10 227492 _ at occludin pseudogene // / 208579 _ x _ at H2B histone family , member S occludin (pseudogene ) // /histone cluster 1558778 _ s _ at MKL /myocardin - like 2 1 , H2bk 31637 _ s _ at nuclear receptor subfamily 1 , 239493 _ at ribosomal protein L7 group D , member 1/ // thyroid 214074 _ s _ at cortactin hormone receptor, alpha 228091 at syntaxin 17 229190 _ at uncharacterized LOC100507376 234331 _ s _ at family with sequence similarity 236188 _ s _ at Nucleosome assembly protein 84 , member A 1 - like 4 . 212372 _ at myosin , heavy chain 10 , non -muscle 212503 _ s _ at DIP2 disco - interacting protein 2 homolog C ( Drosophila ) 20 204760 _ s _ at nuclear receptor subfamily 1 , group D , member 1 // /thyroid Or, from genes for each of the pharmacodynamic hormone receptor, alpha biomarkers from the list further consisting of: 212099 _ at ras homolog family member B 214873 _ at low density lipoprotein receptor related protein 5 - like 25 MMP2 ESR1 FOS PCLG2 MAPK6 228181 _ at solute carrier family 30 ( zinc JUN COND1 PPAR1 MAPK1 MAPK7 transporter ) , member 1 CEBPA MAPK3 PCLG1 MAPK4 MAPK12 212763 _ at calmodulin regulated spectrin AKT2 CASP3 FOS HSP90AB1 JUN associated protein family, BAG3 CCND1 HASP90AA1 HSP90B1 AKT1 member 2 ARG2 CCNA1 CCND2 CCNE2 TNF 226285 at cell cycle associated protein 1 BDNF CCNA2 CCNE1 CTF1 BRAF 213567 _ at karyopherin alpha 4 ( importin ARG2 CCND2 TNF PPP3R1 CALM3 alpha 3 ) BDNF CCNE1 PPP3CA PPP3R2 CAMK1 203927 at nuclear factor of kappa light CCNA1 CCNE2 PPP3CB CALM1 CAMK1D polypeptide gene enhancer in CCNA2 CTF1 PPP3CC CALM2 CAMKIG B - cells inhibitor, epsilon BDNF CCNE1 PPP3CC ORAI3 TNF 208523 _ x _ at histone cluster 1 , H2bc // / CCNA1 PPP3CB CAMK2D CCND2 CALM3 histone cluster 1 , H2belll 30 PPP3?? CACNA2D4 CHRNB3 HDAC10 histone cluster 1 , H2bf/ / /his PPP3CB CACNB1 CHRNB4 HDAC11 219389 _ at sushi domain containing 4 PPP3CC CACNB2 CHRND HDAC2 202329 _ at C - src tyrosine kinase PPP3R1 CACNB3 CHRNE HDAC3 238523 _ at kelch - like 36 ( Drosophila ) PPP3R2 CACNB4 CHRNG HDAC4 1565016 _ at protein arginine ATP2C1 CACNG1 GRIA1 HDAC5 methyltransferase 1 40 CACNA1A CHRFAMA GRIA2 HDAC6 226409 _ at TBC1 domain family , member CACNAIB CHRNA1 GRIA3 HDAC7 20 CACNAIC CHRNA10 GRIA4 HDACS 229926 _ at microRNA 3682 CACNAID CHRNA2 GRIK1 HDAC9 208527 _ x _ at histone cluster 1 , H2bc // / CACNA1F CHRNA3 GRIN1 HTR3A histone cluster 1 , H2bell / CACNAIH CHRNAS GRIN2B SLC8A1 histone cluster 1 , H2bf/ / /his 45 CACNA2I CHRNA6 GRIN2C TNNC1 223598 at RAD23 homolog B ( S . CACNAIG CHRNA4 GRIN2A RYR1 cerevisiae ) CACNAIS CHRNAZ GRIN2D 243797 _ at serine / threonine kinase 17b CACNA2D1 CHRNAS GRINJA 203317 at pleckstrin and Sec7 domain CACNA2D2 CHRNB1 GRINGB containing 4 CACNA2D3 CHRNB2 HDAC1 230965 _ at ubiquitin specific peptidase 2 CACNA2D1 CHRNA9 GRINJA 208490 _ x _ at histone cluster 1 , H2bc / / / 0 histone cluster 1 , H2be // / CACNA2D2 CHRNB1 GRIN3B histone cluster 1 , H2bf: // his CACNA2D3 CHRNB2 HDACC1 235514 at aspartic peptidase , retroviral MAP15 AKT1 MOS3 HSP90B1 like 1 CASP3 ???2 HSP90AA1 Hsp 84 - 2 209098 _ s _ at jagged 1 HSPA8 ???? HSP90AB1 Hsp 84 - 3 1554229 _ at CREB3 regulatory factor 55 BAG3 209398 _ at histone cluster 1 , H1c CEBPA MAPK3 202629 _at amyloid beta precursor protein MAPK1 MAPK7 ( cytoplasmic tail) binding CA9 protein 2 CALR 203428 _ s _ at ASF1 anti - silencing function 1 CAMK2A CAMK4 ORAI3 TRPC3 TRPC7 homolog A ( S . cerevisiae ) 60 CAMK2B NOS2 STIM1 TRPC4 BRAF 238005 _ s _ at SIN3 transcription regulator CAMK2D ORAI2 STIM2 TRPC5 CA9 homolog A (yeast ) CAMK2G ORAI2 TRPC1 TRPC6 CALR 214455 at histone cluster 1 , H2bc / / / CAMK1 ORAI2 BRAF histone cluster 1 , H2be/ // CAMK2G STIM2 CALR histone cluster 1 , H2bf7 / / his 214073 _ at cortactin 65 203140 at B - cell CLL / lymphoma 6 Or, from genes for each of the pharmacodynamic biomarkers from the list further consisting of: US 10 , 378 , 059 B2 67 68 9 . The method of claim 1, wherein at least one of the ABCC5 CYHR1 HIST3H2A POU2F3 signature pathways is HDAC . AT?6?1?1 DEPTOR HOXB13 RAMP1 ATXN3 DNAL4 ING4 SEMA3G 10 . The method of claim 9 , wherein the signature score of BCAS1 EIF4A2 OVGP1 SEPP1 the pharmacodynamic biomarkers of the signature pathways BCL2L11 EPHX2 PCMTD1 SIDT2 5 for HDAC is inhibited in response to exposure to CTO . CALCOCO1 ERBB3 PCMTD2 AREG CAPN13 HIST1H2AC PDIA4 BTG3 11 . The method of claim 1 , wherein at least one of the CRBN HIST1H2BD PLEKHG4 CEBPG signature pathways is NOTCH . 12. The method of claim 11 , wherein the signature score COROIC IFRD1 PFKP of the pharmacodynamic biomarkers of the signature path DLEU2 IMPAD1 PNPT1 10 DPH3 KLK6 PSMC4 ways for NOTCH is inhibited in response to exposure to EIF5 K???4 RPS6KA3 CTO . ENO2 LRP8 S100A2 13 . The method of claim 1 , wherein at least one of the HN1 MALL SERPINB5 HSP90AA1 MTHFDIL SERPINB8 signature pathways is WNTB -catenin . HSPALL PADI1 SLC7A1 14 . The method of claim 13 , wherein the signature score SRXN1 of the pharmacodynamic biomarkers of the signature path TIPIN ; ways for WNTB -catenin is inhibited in response to exposure to CTO . and 15 . The method of claim 1 , wherein at least one of the d ) identifying , using the calculated signature scores and 20 signature pathways is HSP90 . quantitated responses , each of the pharmacodynamics 16 . The method of claim 15 , wherein the signature score biomarkers of each of the signature pathways by at of the pharmacodynamic biomarkers of the signature path least 3 or more genes listed in 1c ) . ways for HSP90 is inhibited in response to exposure to CTO . 2 . The method of claim 1 , wherein the pharmacodynamic 17 . The method of claim 1, wherein at least one of the biomarkers of each of the signature pathways further include 2525 signature pathways is EGFR . at least 3 or more genes for which pharmacodynamics 18 . The method of claim 17 , wherein the signature score biomarkers are from the list consisting of: of the pharmacodynamic biomarkers of the signature path ways for EGFR is inhibited in response to exposure to CTO . ABCC5 CYHR1 HIST3H2A POU2F3 19 . The method of claim 1 , wherein at least one of the ATP6V1B1 DEPTOR HOXB13 RAMP1 30 signature pathways is P53 . ATXN3 DNAL4 ING4 SEMA3G BCAS1 EIF4A2 OVGP1 SEPP1 20 . The method of claim 19 , wherein the signature score BCL2L11 EPHX2 PCMTD1 SIDT2 of the pharmacodynamic biomarkers of the signature path CALC0001 ERBB3 PCMTD2 AREG ways for P53 is induced in response to exposure to CTO . CAPN13 HIST1H2AC PDIA4 BTG3 CRBN HIST1H2BD PLEKHG4 CEBPG 35 21 . The method of claim 1, wherein at least one of the signature pathways is EGR1 . COROIC IFRD1 PFKP DLEU2 IMPAD1 PNPT1 22 . The method of claim 21 , wherein the signature score DPH3 KLK6 PSMC4 of the pharmacodynamic biomarkers of the signature path EIF5 K???4 RPS6KA3 ways for EGR1 is stimulated in response to exposure to ENO2 LRP8 S100A2 40 CTO . HN1 MALL SERPINB5 HSP9OAA1 MTHFDIL SERPINB8 23 . The method of claim 1 , wherein at least one of the HSPA4L PADI1 SLC7A1 signature is CEACAMI. SRXN1 24 . The method of claim 23 , wherein the signature score TIPIN . of the pharmacodynamic biomarkers of the signature path 45 ways for CEACAMI is stimulated in response to exposure to 3 . The method of claim 2 , wherein at least one of the CTO . signature pathways is RAS. 25 . The method of claim 1, wherein at least one of the 4 . The method of claim 3 , wherein the signature score of signature pathways is TGFB . the pharmacodynamic biomarkers of the signature pathways 26 . The method of claim 25 , wherein the signature score for RAS is inhibited in response to exposure to CTO of the pharmacodynamic biomarkers of the signature path 5 . The method of claim 2 , wherein at least one of the ways for TGFB is stimulated in response to exposure to signature pathways is GFS . CTO . 6 . The method of claim 5 , wherein the signature score of the pharmacodynamic biomarkers of the signature pathways 27 . The method of claim 1 , wherein at least one of the for GFS is inhibited in response to exposure to CTO . 55 signature pathways is Dystonin . 7 . The method of claim 1 , wherein at least one of the 28 . The method of claim 27 , wherein the signature score signature pathways is MEKi. of the pharmacodynamic biomarkers of the signature path 8 . The method of claim 5 , wherein the signature score of ways for Dystonin is stimulated in response to exposure to the pharmacodynamic biomarkers of the signature pathways CTO . for MEKi is inhibited in response to exposure to CTO . * * * * *