New Contributions in Undergraduate Research
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The Drug Sensitivity and Resistance Testing (DSRT) Approach
A phenotypic screening and machine learning platform eciently identifies triple negative breast cancer-selective and readily druggable targets Prson Gautam 1 Alok Jaiswal 1 Tero Aittokallio 1, 2 Hassan Al Ali 3 Krister Wennerberg 1,4 Identifying eective oncogenic targets is challenged by the complexity of genetic alterations in 1Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Finland cancer and their poorly understood relation to cell function and survival. There is a need for meth- Current kinome coverage of kinase inhibitors in TNBC exhibit diverse kinase dependencies MFM-223 is selectively addicted to FGFR2 2Department of Mathematics and Statistics, University of Turku, Finland 3The Miami Project to Cure Paralysis, Peggy and Harold Katz Family Drug Discovery Center, A A Sylvester Comprehensive Cancer Center, and Department of Neurological Surgery and Medicine ods that rapidly and accurately identify “pharmacologically eective” targets without the require- clinical evaluation TN Kinases MFM-223 CAL-120 MDA-MB-231 TNBC TNBC TNBC TNBC TNBC TNBC HER2+ 100 University of Miami Miller School of Medicine, Miami, FL 33136, USA. non- HER2+ FGFR1 0.97 0.00 0.00 MFM-223 BL1 BL2 M MSL IM LAR ER+, PR+ 50 ment for priori knowledge of complex signaling networks. We developed an approach that uses ma- cancerous FGFR2 56.46 0.00 0.00 CAL-120 25 4 MDA-MB-231 Biotech Research & Innovation Centre (BRIC) and Novo Nordisk Foundation Center HCC1937 CAL-85-1 CAL-120 MDA-MB-231 DU4475 CAL-148 MCF-10A SK-BR-3 BT-474 FGFR3 25.10 0.00 0.00 0 chine learning to relate results from unbiased phenotypic screening of kinase inhibitors to their bio- for Stem Cell Biology (DanStem), University of Copenhagen, Denmark HCC1599 HDQ-P1 BT-549 MDA-MB-436 MFM-223 FGFR4 0.00 0.00 0.00 MAXIS*Bk Clinical status MDA-MB-468 CAL-51 Hs578T MDA-MB-453 score chemical activity data. -
Biological Heterogeneity of Chondrosarcoma: from (Epi) Genetics Through Stemness and Deregulated Signaling to Immunophenotype
cancers Review Biological Heterogeneity of Chondrosarcoma: From (Epi) Genetics through Stemness and Deregulated Signaling to Immunophenotype Agnieszka Zaj ˛ac 1 , Sylwia K. Król 2 , Piotr Rutkowski 1 and Anna M. Czarnecka 1,3,* 1 Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; [email protected] (A.Z.); [email protected] (P.R.) 2 Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; [email protected] 3 Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-176 Warsaw, Poland * Correspondence: [email protected] Simple Summary: Chondrosarcoma (ChS) is the second most frequently diagnosed malignant bone tumor of cartilaginous origin and is generally resistant to standard treatment options. In this paper, we aim to review the current state of the knowledge regarding ChS. We discuss the genetic, epigenetic, and molecular abnormalities underlying its substantial biological and clinical heterogeneity. This review summarizes the critical genetic and molecular drivers of ChS development and progression, contributing to its radio- and chemotherapy resistance. We describe genomic aberrations and point mutations, as well as epigenetic modifications and deregulated signal transduction pathways. We Citation: Zaj ˛ac,A.; Król, S.K.; provide an insight into the stem-like characteristics and immunophenotype of ChS. The paper also Rutkowski, P.; Czarnecka, A.M. outlines potential diagnostic and prognostic biomarkers of ChS and recently identified novel targets Biological Heterogeneity of for future pharmacological interventions in patients. Chondrosarcoma: From (Epi) Genetics through Stemness and Abstract: Deregulated Signaling to Chondrosarcoma (ChS) is a primary malignant bone tumor. -
Chronic Lymphocytic Leukemia
Amsterdam, the Netherlands, June 14 – 17, 2012 Chronic lymphocytic leukemia - Clinical 1 assumed efficacy especially in high-risk situations (early relapse, unfavourable prognostic markers), was used in 202 patients. The overall survival in the CHOP-collective was significantly shorter than in the comparative group (p<0.0001) although median observation time was not significantly differ - 0144 ent. However, this observation might reflect a bias in the selection of high risk patients for this relapse treatment. No influence on survival was INFLUENCE OF DIFFERENT TREATMENT REGIMENS ON SURVIVAL IN observed in patients receiving a mitoxantrone-containing regimen at any PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA - A META-ANALY - time during the treatment course. Summary and Conclusions. This meta- SIS OF THE GERMAN CLL STUDY GROUP (GCLLSG) analysis shows that the advances in the development of strategies for first- S Isfort 1, P Cramer 2, J Bahlo 2, R Busch 3, K Fischer 2, AM Fink 2, V Goede 2, T line therapies result in prolongation of treatment-free and overall survival Elter 2, M Bergmann 4, M Stauch 5, S Stilgenbauer 4, CM Wendtner 6, M Hallek 2, for patients with CLL and need of treatment. Chemoimmunotherapies pro - B Eichhorst 2 long the survival independently of the time point of chemoimmunotherapy 1Department of Medicine IV, University Hospital Aachen, Aachen, Germany administration (for first-line therapy or relapse). 2Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany 3 Institute for Medical Statistic and Epidemiology, Technical University Munich, 0145 Munich, Germany 4 Department III of Internal Medicine, University Hospital Ulm, Ulm, Germany A SINGLE-ARM MULTI-CENTER TRIAL OF BENDAMUSTINE GIVEN 5 Private practice and day time clinic for Hematology and Oncology, Kronach, WITH OFATUMUMAB (BENDOFA) IN PATIENTS WITH REFRACTORY OR Kronach, Germany RELAPSED CHRONIC LYMPHOCYTIC LEUKEMIA. -
National Cancer Institute Cancer National
DIVISION OF CANCER TREATMENT AND DIAGNOSIS National Cancer Institute Cancer National PROGRAM ACCOMPLISHMENTS 2006 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health TABLE OF CONTENTS Foreword . iii Division of Cancer Treatment and Diagnosis Overview . .1 Major Ongoing Initiatives and Accomplishments . .7 Biometric Research Branch Overview . 11 Partnerships and Collaborations . 12 Scientific Advances . 17 Other Biostatistical Research . 24 Tools, Products, and Resources . 27 Cancer Diagnosis Program Overview . 29 Major Ongoing Initiatives . 30 Current Funding Opportunities . 34 Partnerships and Collaborations . 36 Scientific Advances . 39 Tools, Products, and Resources . 41 Cancer Imaging Program Overview . 45 Major Ongoing Initiatives . 47 Current Funding Opportunities . 54 Partnerships and Collaborations . 57 Scientific Advances . 61 Tools, Products, and Resources . 63 Cancer Therapy Evaluation Program Overview . 65 Major Ongoing Initiatives . 67 Significant Ongoing Clinical Trials . 71 Current Funding Opportunities . 73 Partnerships and Collaborations . 75 Scientific Advances . 79 Tools, Products, and Resources . 92 TABLE OF CONTENTS ■ i Developmental Therapeutics Program Overview . 95 New Initiatives . 97 Major Ongoing Initiatives . .100 Current Funding Opportunities . .104 Tools, Products, and Resources . .105 History-Marking Event . .114 Scientific Advances . .115 Radiation Research Program Overview . .119 Partnerships and Collaborations . .121 Scientific Advances . .127 Tools, Products, and Resources . .129 -
Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia
Published OnlineFirst September 20, 2013; DOI: 10.1158/2159-8290.CD-13-0350 RESEARCH ARTICLE Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia Tea Pemovska 1 , Mika Kontro 2 , Bhagwan Yadav 1 , Henrik Edgren 1 , Samuli Eldfors1 , Agnieszka Szwajda 1 , Henrikki Almusa 1 , Maxim M. Bespalov 1 , Pekka Ellonen 1 , Erkki Elonen 2 , Bjørn T. Gjertsen5 , 6 , Riikka Karjalainen 1 , Evgeny Kulesskiy 1 , Sonja Lagström 1 , Anna Lehto 1 , Maija Lepistö1 , Tuija Lundán 3 , Muntasir Mamun Majumder 1 , Jesus M. Lopez Marti 1 , Pirkko Mattila 1 , Astrid Murumägi 1 , Satu Mustjoki 2 , Aino Palva 1 , Alun Parsons 1 , Tero Pirttinen 4 , Maria E. Rämet 4 , Minna Suvela 1 , Laura Turunen 1 , Imre Västrik 1 , Maija Wolf 1 , Jonathan Knowles 1 , Tero Aittokallio 1 , Caroline A. Heckman 1 , Kimmo Porkka 2 , Olli Kallioniemi 1 , and Krister Wennerberg 1 ABSTRACT We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profi ling and ex vivo drug sensitivity and resistance testing (DSRT) of patients’ cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered fi ve major taxonomic drug-response sub- types based on DSRT profi les, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3 -ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. -
( 12 ) United States Patent
US010624968B2 (12 ) United States Patent (10 ) Patent No.: US 10,624,968 B2 Bennett et al. (45 ) Date of Patent : Apr. 21 , 2020 ( 54 ) COMPOUNDS FOR TREATING CANCER WO 2005113554 12/2005 WO 2006078161 7/2006 WO 2006078846 7/2006 (71 ) Applicant: Bicycle Therapeutics Limited , WO 2006122806 11/2006 Cambridge (GB ) WO 2007016176 2/2007 WO 2007044729 4/2007 ( 72 ) Inventors : Gavin Bennett , Cambridge (GB ) ; WO 2007053452 5/2007 Daniel Paul Teufel , Cambridge (GB ) WO 2007070514 6/2007 WO 2007084786 7/2007 WO 2007129161 11/2007 ( 73 ) Assignee : BICYCLERD LIMITED , Cambridge WO 2008039218 4/2008 (GB ) WO 2008109943 9/2008 WO 2008118802 10/2008 ( * ) Notice : Subject to any disclaimer, the term of this WO 2009098450 8/2009 patent is extended or adjusted under 35 WO 2009114512 9/2009 WO 2010089115 8/2010 U.S.C. 154 ( b ) by 0 days . WO 2011090760 7/2011 WO 2013050615 4/2013 (21 ) Appl. No.: 15 /862,964 WO 2016067035 5/2016 WO 2017191460 11/2017 ( 22 ) Filed : Jan. 5 , 2018 WO 2018127699 7/2018 (65 ) Prior Publication Data OTHER PUBLICATIONS US 2018/0200378 A1 Jul. 19 , 2018 Paul Polakis . Antibody Drug Conjugates for Cancer Therapy. Pharmacol Rev. Jan 1 , 2016 ;68 ( 1 ) :3-19 . ( Year: 2016 ) . * Related U.S. Application Data Heinis et al. Phage- encoded combinatorial chemical libraries based (60 ) Provisional application No. 62/ 443,508, filed on Jan. on bicyclic peptides . Nat Chem Biol, 2009 ; 5 ( 7 ) : 502-07. ( Year: 2009) . * 6 , 2017 Eder et al. A phage display derived stabilised bicyclic peptide (51 ) Int. Ci. targeting MMP- 14 shows high imaging contrast in small animal A61K 47/64 ( 2017.01 ) PET imaging. -
( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2020/0206143 A1
US 20200206143A1 IN (19 ) United States ( 12) Patent Application Publication (10 ) Pub . No.: US 2020/0206143 A1 Moskowitz et al. (43 ) Pub . Date : Jul. 2 , 2020 ( 54 ) PLATELETS LOADED WITH ANTI - CANCER Publication Classification AGENTS (51 ) Int. Ci. A61K 9/50 (2006.01 ) ( 71 ) Applicant: Cellphire, Inc., Rockville , MD (US ) A61K 31/704 (2006.01 ) ( 72 ) Inventors : Keith Andrew Moskowitz , Westfield , A61K 31/502 ( 2006.01 ) IN (US ) ; Rafael Jorda, Bethesda, MD A61K 31/337 (2006.01 ) (US ) ; Ying Yi Zheng , Rockville , MD AOIN 1/02 ( 2006.01) (US ) ; Daniel Sheik , Rockville , MD A61K 9/127 (2006.01 ) (US ) (52 ) U.S. CI. CPC A61K 9/5068 ( 2013.01 ) ; A61K 31/704 (2013.01 ) ; A61K 31/502 ( 2013.01) ; AOIN ( 21 ) Appl. No .: 16 /698,645 1/021 ( 2013.01 ) ; AOIN 1/0226 (2013.01 ) ; A61K 9/1271 (2013.01 ) ; A61K 31/337 ( 22 ) Filed : Nov. 27 , 2019 (2013.01 ) ( 57 ) ABSTRACT Related U.S. Application Data In some embodiments provided herein is a method of (60 ) Provisional application No. 62 / 773,931, filed on Nov. preparing cargo - loaded platelets , comprising : treating plate 30 , 2018 , provisional application No. 62/ 775,141 , lets with a cargo and with a loading buffer comprising a salt , filed on Dec. 4 , 2018, provisional application No. a base , a loading agent , and optionally ethanol, to form the 62 /828,041 , filed on Apr. 2 , 2019 . cargo - loaded platelets . Patent Application Publication Jul. 2 , 2020 Sheet 1 of 20 US 2020/0206143 A1 Amount of Doxorubicin (DOX ) load per CD42b * Platelet DOX(mfi) FIG . 1 Amount of DOX in drug loaded platelets following ADP and /or TRAP stimulation 227 FIG . -
Supporting Information
Supporting Information Pouryahya et al. SI Text Table S1 presents genes with the highest absolute value of Ricci curvature. We expect these genes to have significant contribution to the network’s robustness. Notably, the top two genes are TP53 (tumor protein 53) and YWHAG gene. TP53, also known as p53, it is a well known tumor suppressor gene known as the "guardian of the genome“ given the essential role it plays in genetic stability and prevention of cancer formation (1, 2). Mutations in this gene play a role in all stages of malignant transformation including tumor initiation, promotion, aggressiveness, and metastasis (3). Mutations of this gene are present in more than 50% of human cancers, making it the most common genetic event in human cancer (4, 5). Namely, p53 mutations play roles in leukemia, breast cancer, CNS cancers, and lung cancers, among many others (6–9). The YWHAG gene encodes the 14-3-3 protein gamma, a member of the 14-3-3 family proteins which are involved in many biological processes including signal transduction regulation, cell cycle pro- gression, apoptosis, cell adhesion and migration (10, 11). Notably, increased expression of 14-3-3 family proteins, including protein gamma, have been observed in a number of human cancers including lung and colorectal cancers, among others, suggesting a potential role as tumor oncogenes (12, 13). Furthermore, there is evidence that loss Fig. S1. The histogram of scalar Ricci curvature of 8240 genes. Most of the genes have negative scalar Ricci curvature (75%). TP53 and YWHAG have notably low of p53 function may result in upregulation of 14-3-3γ in lung cancer Ricci curvatures. -
Draft COMP Agenda 16-18 January 2018
12 January 2018 EMA/COMP/818236/2017 Inspections, Human Medicines Pharmacovigilance and Committees Committee for Orphan Medicinal Products (COMP) Draft agenda for the meeting on 16-18 January 2018 Chair: Bruno Sepodes – Vice-Chair: Lesley Greene 16 January 2018, 09:00-19:30, room 2F 17 January 2018, 08:30-19:30, room 2F 18 January 2018, 08:30-18:30, room 2F Health and safety information In accordance with the Agency’s health and safety policy, delegates are to be briefed on health, safety and emergency information and procedures prior to the start of the meeting. Disclaimers Some of the information contained in this agenda is considered commercially confidential or sensitive and therefore not disclosed. With regard to intended therapeutic indications or procedure scopes listed against products, it must be noted that these may not reflect the full wording proposed by applicants and may also vary during the course of the review. Additional details on some of these procedures will be published in the COMP meeting reports once the procedures are finalised. Of note, this agenda is a working document primarily designed for COMP members and the work the Committee undertakes. Note on access to documents Some documents mentioned in the agenda cannot be released at present following a request for access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on- going procedures for which a final decision has not yet been adopted. They will become public when adopted or considered public according to the principles stated in the Agency policy on access to documents (EMA/127362/2006). -
(PI3K) in Head and Neck Squamous Cell Carcinoma (HNSCC) Kyungsuk Jung1* , Hyunseok Kang2 and Ranee Mehra2
Jung et al. Cancers of the Head & Neck (2018) 3:3 Cancers of the https://doi.org/10.1186/s41199-018-0030-z Head & Neck REVIEW Open Access Targeting phosphoinositide 3-kinase (PI3K) in head and neck squamous cell carcinoma (HNSCC) Kyungsuk Jung1* , Hyunseok Kang2 and Ranee Mehra2 Abstract: The landscape of head and neck squamous cell carcinoma (HNSCC) has been changing rapidly due to growing proportion of HPV-related disease and development of new therapeutic agents. At the same time, there has been a constant need for individually tailored treatment based on genetic biomarkers in order to optimize patient survival and alleviate treatment-related toxicities. In this regard, aberrations of PI3K pathway have important clinical implications in the treatment of HNSCC. They frequently constitute ‘gain of function’ mutations which trigger oncogenesis, and PI3K mutations can also lead to emergence of drug resistance after treatment with EGFR inhibitors. In this article, we review PI3K pathway as a target of treatment for HNSCC and summarize PI3K/mTOR inhibitors that are currently under clinical trials. In light of recent advancement of immune checkpoint inhibitors, consideration of PI3K inhibitors as potential immune modulators is also suggested. Keywords: HNSCC, PI3K, mTOR, Akt, EGFR, PIK3CA, HPV, Drug resistance, Precision medicine Background related HNSCC frequently harbors mutations in the hel- Head and neck squamous cell carcinoma (HNSCC) ical domain of PIK3CA, yet its biological significance arises from mucosal epithelium of oral cavity, pharynx has not been fully elucidated. In the era of precision and larynx. An estimate of 61,000 new cases of HNSCC medicine, it is becoming more important to understand were diagnosed in the US in 2016, with 13,190 deaths at- key genomic alterations and their therapeutic implica- tributable to the disease [1]. -
Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG . -
Phenotype-Based Drug Screening Reveals Association Between Venetoclax Response and Differentiation Stage in Acute Myeloid Leukemia
Acute Myeloid Leukemia SUPPLEMENTARY APPENDIX Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia Heikki Kuusanmäki, 1,2 Aino-Maija Leppä, 1 Petri Pölönen, 3 Mika Kontro, 2 Olli Dufva, 2 Debashish Deb, 1 Bhagwan Yadav, 2 Oscar Brück, 2 Ashwini Kumar, 1 Hele Everaus, 4 Bjørn T. Gjertsen, 5 Merja Heinäniemi, 3 Kimmo Porkka, 2 Satu Mustjoki 2,6 and Caroline A. Heckman 1 1Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki; 2Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, Helsinki; 3Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland; 4Department of Hematology and Oncology, University of Tartu, Tartu, Estonia; 5Centre for Cancer Biomarkers, De - partment of Clinical Science, University of Bergen, Bergen, Norway and 6Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland ©2020 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol. 2018.214882 Received: December 17, 2018. Accepted: July 8, 2019. Pre-published: July 11, 2019. Correspondence: CAROLINE A. HECKMAN - [email protected] HEIKKI KUUSANMÄKI - [email protected] Supplemental Material Phenotype-based drug screening reveals an association between venetoclax response and differentiation stage in acute myeloid leukemia Authors: Heikki Kuusanmäki1, 2, Aino-Maija