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(19) United States (12) Patent Application Publication (10) Pub US 20120149714A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0149714 A1 Heise et al. (43) Pub. Date: Jun. 14, 2012 (54) EFFECTS OF INHIBITORS OF FGFR3 ON (60) Provisional application No. 60/748,944, ?led on Dec. GENE TRANSCRIPTION 8, 2005. (76) Inventors: Carla Heise, Benicia, CA (US); Publication Classi?cation Esther Masih-Khan, Ontario (CA); 51 I Cl Edward Moler Walnut Creek CA ( ) nt' ' (US); Michael. Rowe,’ Oakland,’ CA A61K 31/497 (2006.01) (US),_ Keith. Stewart, Scottsdale, G01N 33/53 (2006.01) AZ (US) Suzanne Trudel Ontario G01N 33/566 (200601) (CA) ’ ’ C12Q 1/68 (2006.01) (52) US. Cl. ................ .. 514/253.07; 435/611; 435/612; (21) Appl. No.: 13/400,833 435/79; 435/792; 436/501 (22) Filed: Feb. 21, 2012 (57) ABSTRACT Related U‘s‘ Application Data Methods of utilizing blomarkers to 1dent1fy patients for treat ment or to momtor response to treatment are taught herein. (62) Division of application No, 12/096,222, ?led on Jun, Alterations in levels of gene expression of the biomarkers, 19, 2008, now Pat. No. 8,158,360, ?led as application particularly in response to FGFR3 inhibition, are measured No. PCT/US2006/061766 on Dec. 7, 2006. and identi?cations or adjustments may be made accordingly. US 2012/0149714 A1 Jun. 14, 2012 EFFECTS OF INHIBITORS OF FGFR3 ON [0007] An individual’s response to a particular treatment or GENE TRANSCRIPTION predisposition to disease and the correlation to a particular gene of interest has been documented. It is noW believed that BACKGROUND OF THE INVENTION cancer chemotherapy is limited by the predisposition of spe ci?c populations to drug toxicity or poor drug response. For a [0001] The present invention relates generally to the ?eld of revieW of the use of germline polymorphisms in clinical pharmacogenomics and in particular to the use of biomarkers oncology, see LenZ, H.-J. (2004) J. Clin. Oncol. 22(1 3):25 l 9 for identifying patients suitable for treatment as Well as to 2521 . For a revieW of pharmacogenctic and pharmacogenom methods of following their response to methods of treatment. ics in therapeutic antibody development for the treatment of [0002] An effort to understand an individual patient’s cancer, see Yan and Beckman (2005) Biotechniques 39:565 response or disease progression is the topic of present day 568. research. Indeed, the ?eld of pharmacogenomics or pharma [0008] Results from numerous studies suggest several cogenetics utiliZes genomic data, pharmacology, and medi genes may play a major role in the principal pathWays of cine, and often relies on advanced research tools to correlate cancer progression and recurrence, and that the correspond genetic variability to one or more of predisposition to a dis ing germ-line polymorphisms may lead to signi?cant differ ease and/or its progression, as Well as therapeutic response to ences at transcriptional and/or translational levels. Polymor a drug or therapeutic regimen. Typically, multiple genes are phism has been linked to cancer susceptibility (oncogenes, analyZed simultaneously in a large-scale, genome-Wide tumor suppressor genes, and genes of enZymes involved in approach. metabolic pathWays) of individuals. In patients younger than [0003] Proliferative cell disorders such as cancers usually 35 years, several markers for increased cancer risk have been develop through the accumulation of a series of mutations in identi?ed. Cytochrome P4501Al and gluthathione S-trans the patient’s DNA Within a subpopulation of cells. These ferase Ml genotypes in?uence the risk of developing prostate mutations may confer a survival advantage on the cells that cancer in younger patients. Similarly, mutations in the tumor causes them to groW and spread in an uncontrolled manner suppressor gene, p53, are associated With brain tumors in that is deleterious to the surrounding tissues. The particular young adults. set of mutations may be unique to an individual patient’s [0009] This approach may be extended to mutations that tumor. Cancers of the same tissue or organ in different indi are speci?c to cancer cells, and not otherWise found in the viduals may have originated from different sets of mutations, patient’s genome. For instance, it has been demonstrated though certain mutations may be prevalent among particular clinically in patients With gastrointestinal stromal tumors cancer types. The characteristic set of mutations Will deter (GIST) treated With the drug Gleevec (imatinib mesylate; mine hoW the cancer cells behave, and in particular, their Novartis) that particular activating mutations in the genes likelihood of response to a given therapeutic regimen. KIT and PDGFA are linked to higher response rates to the [0004] One may characterize the genetic alterations in a drug, see JClin Oncol. 2003 Dec. 1; 2l(23):4342-9. tumor by using advanced research tools that measure the [0010] By measuring changes in gene expression of cancer genetic sequence of the tumor’s DNA, or the RNA or proteins cell lines induced by treatment With a particular therapeutic that are the expression of the altered DNA. It is a goal of agent, one may characteriZe the cells’ response to that agent. current research to identify characteristics of an individual’s This approach provides insight into the mechanism of the tumor that are predictive of the likelihood of that tumor’s drug, including What biological processes or pathWays it response to various therapeutic treatments. Thus, one or more impacts. Such information can help guide the treatment of genes Would be identi?ed Where presence of particular patients, by providing expectations as to Which genes Will genetic mutations in the DNA, or their levels of expression, change in response to treatment. An assay of those genes from either as RNA transcripts or as proteins, or a combination of a sample collected from a patient post-treatment could then these factors, Would be predictive of the likelihood that a be used to determine Whether the drug Was having the particular treatment Would affect the tumor in a manner that intended effect, and by extension, Whether the dose or sched Would be bene?cial to the patient. ule should be altered, or the regimen discontinued. This [0005] One main purpose is to determine Which variations approach Would improve e?icacy by ensuring that patients receive the most appropriate treatment. in individuals or subpopulations, associated With their genet ics or the genetic characteristics of their disease, factor into drug e?icacy and to create suitable tests, including diagnostic SUMMARY OF THE INVENTION tests. Drugs that are tailored for patients With a particular [0011] One embodiment of the invention relates to a genetic sequence, or for diseases characterized by particular method of identifying a patient for treatment. The method genetic alterations, may thus be produced. The tests may also may optionally include an administration of an FGFR3 be used to guide treatment decisions, such as Which drug or inhibitor to the patient prior to measurement of gene expres drug combination is mostly likely to be bene?cial to the sion on a sample obtained from the patient. The gene expres patient, and What dosing and schedule is most appropriate. sion analysis is intended to detect the presence and/ or alter Diagnostic tests and genetic pro?ling Will help avoid the ation in level of expression of biomarkers disclosed herein. expense and the potentially detrimental trial-and-error Notable detection or alteration in the levels compared to approach to the suitability of a particular treatment regimen or baseline levels is indicative of the candidacy of the patient for a particular dosage level. treatment. [0006] While the era of customiZed drugs may be coming, [0012] Another embodiment of the invention comprises a methods that utiliZe genetic information to identify speci?c method of monitoring response of a patient to treatment. The individuals or subgroups for a particular type of treatment or method may include the step of administration of an FGFR3 optimiZation of a treatment may be immediately put to use inhibitor to the patient prior to measurement of gene expres today. sion on a sample obtained from the patient. Alternatively, US 2012/0149714 A1 Jun. 14, 2012 monitoring may be conducted on a sample obtained from a explicitly stated, that the reagents described herein are merely patient Who has previously been treated so that an adminis exemplary and that equivalents of such are knoWn in the art. tration step by one practicing the method of monitoring [0022] The terms “polynucleotide” and “oligonucleotide” response is not required. Detection of an alteration in the level are used interchangeably and refer to a polymeric form of of expression of at least one biomarker compared to baseline nucleotides of any length, either deoxyribonucleotides or is indicative of a favorable response of the patient to the ribonucleotides or analogs thereof. Polynucleotides can have treatment. any three-dimensional structure and may perform any func [0013] Another aspect of the invention is a method of uti tion, knoWn or unknown. The folloWing are non-limiting liZing a biomarker in treatment of a patient. An FGFR3 inhibi examples of polynucleotides: a gene or gene fragment (for tor may be administered and gene expression level of one or example, a probe, primer, EST or SAGE tag), exons, introns, more biomarkers tested. Thereafter, the same or a different messenger RNA (mRNA), transfer RNA, ribosomal RNA, inhibitor may be administered in the treatment. riboZymes, cDNA, recombinant polynucleotides, branched [0014] Yet another aspect of the invention is a method of polynucleotides, plasmids, vectors, isolated DNA of any treatment for multiple myeloma. The method utiliZes an agent sequence, isolated RNA of any sequence, nucleic acid probes, that alters the level of expression of one or more of the and primers.
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