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Translating Lymphoma Genetics into Clinical Care

Translating Lymphoma Genetics into Clinical Care. Thorsten Zenz , MD Dept . of Translational Oncology , National Center for Tumor Diseases (NCT) / German Cancer Research Center (DKFZ), Heidelberg

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Translating Lymphoma Genetics into Clinical Care

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  1. TranslatingLymphomaGeneticsinto Clinical Care Thorsten Zenz, MD Dept. ofTranslationalOncology, National Center for Tumor Diseases (NCT) / German Cancer Research Center (DKFZ), Heidelberg Dept. ofHaematology / Oncology / RheumaticDisease, University Hospital Heidelberg thorsten.zenz@nct-heidelberg.de

  2. ChronicLymphocyticLeukemia (CLL) pathogenesis Straightforwarddiagnosis (CD20dim, CD5+, CD23+, …) Growinglistofgenemutations (ATM, p53, SF3B1, NOTCH1, BIRC3, BRAF,…) BCR-signalling promising target (with potential tochangeclinicalpractice) BTK, Bruton's tyrosine kinase; PI3K, phosphoinositide 3-kinase; SYK, spleen tyrosine kinase. Zenz T, et al. Nat Rev Cancer 2010;10:37–50.

  3. Understanding p53 in CLL anddrugresistance • (Blood 2008; Blood 2009a; Blood 2009b; Leukemia 2010; Blood 2011) Definingclinicalconsequencesofgenetics in CLL (Leukemia 2008;Blood 2008; Blood 2009; JCO 2010; Lancet 2010;Nature Reviews Cancer 2010; Leukemia 2012; Blood 2012) Developingstrategiestoovercomedrugresistance (Cancer Research 2009; Blood 2010; Blood 2011) Prior Work: CLL Geneticanalysis Clinical impact Guidance

  4. ComprehensiveGenetic Profiling Molecularly Aided Stratification for Tumor ERadication Umbrella Protocol for Implementing Personalized Oncology at NCT Consents Every Patient for: Molecular Analysis Data Storage Clinical Data Analysis Re-Contact for Clinical Trials

  5. Genomicsofdrugsensitivity in (primary) lymphoma Mapandidentifydrugsensitivity in leukemias/lymphoma Guiltbyassociation (drug – disease - patient) Synergy, combinationandresponseprediction Trial & clinicalcare in rare diseases

  6. Strategy Parallel molecular and functional characterization • Functional profiling • Pathway inhibition screen Understand diseasebiology 48h Leukemia cells Cellseeding ATP-levels Understand drugsensitivity • Molecular profiling • Genome (Exome + CNV) • Transcriptome • Epigenome Compoundlibraries Rapid clinical translation

  7. Atlas of drug sensitivity in CLL • Custom “pilot” library (67 substances) • Drugs in clinical use • Key CLL/cancer pathway inhibitors • Hits from CLL drug screens >100 patients screened • Prestwick Library: 1120 FDA-approved drugs • Quick clinical translation 36 patients screened • NIH Phase I-III Library: 731 compounds • Main targets known, toxicity data 36 patients screened • GSK Kinase Library 1& 2: 367+512 small molecules • Well characterized targets (220 kinase assays) 36 patients screened • Cooperation partners (LDC, München, Freiburg, Essen)

  8. Screen-wide quality metrics (n=20) 18 Plates 127-144 P0033 (T-PLL)

  9. Mapping patients by drug response Validation screen: 111 patients T-PLL n=5 Healthy MNCs n=3 Resistant CLL n=3 Patients Compounds Less sensitive More sensitive

  10. Mapping patients by drug response Validation screen: 111 patients CLL mutTP53 Patients CLL mutTP53 Compounds Less sensitive More sensitive

  11. Clustering of drugs with same/similar mode of action p53: Fludarabine Nutlin mTOR: Everolimus Deferolimus Kinase inibitors: Saracatinib Dasatinib PKI-402 Selumetinib Tipifarnib etc. drugs drugs

  12. TP53 mutationandsurvival in CLLCLL4 Trial F vs. FC (n=340) Overall survival No 17p-/TP53 Mutation (n=310) TP53 Mutation only (n=14) 17p- (n=16) Zenz et al, JCO, 2010

  13. p53-dependent compounds TP53wt: n=80 TP53mut: n=17 Ex vivo sensitivity reflects biology and clinical observation

  14. Opportunities to map p53 pathway DNA damage ATM ARF MDM2 p53 p21 PUMA or BAX miR-34a Cell cycle arrest Apoptosis DNA repair Senescence Zenz, et al. Nat Rev Cancer 2010

  15. Targeting Key Signaling Pathways in CLL 571300080995 Membrane-boundimmunoglobulin CD20 B-cellreceptor Fostamatinib GS-9973 Lyn CD20 PI3K/Akt pathway Syk Ibrutinib CC-292 Btk NF-κB pathway MAPK pathway Idelalisib IPI-145 TGR-1202 Bcl-2 All are small molecule inhibitors except GA101, which is a monoclonal antibody Cell survival NormalB-cellactivationandproliferation Malignant B-cellinitiationandprogression Friedman and Weinberg. The Hematologist. May 1, 2013.

  16. MutatedandunmutatedIGHV Zenz et al, Nature Reviews Cancer, 2010; Hallek et al, Lancet 2010

  17. Response to BTK inhibitors Byrd et al, NEJM 2013

  18. BCR dependency (BTK inhibitor) Abilityto pick upsubtlefindings (similardata in clinicaltrials (Byrd et al NEJM 2013)) Includingdifferences e.g. Ibrutinib & CC-292

  19. Synergyscreenwith adaptive design 32 inhibitors (5 concentrations) + Control + Ibrutinib0.1µM + Ibrutinib 1µM CC-292 (btk) GS-1101 (PI3K) IPI-454 (PI3K) + R406 (Syk) …. Eachcomparisonwith 32 x 5 x 4 = 640 datapoints

  20. T-PLL rare postthymic T-cell malignancy recurrent inv(14)/t(14;14) or t(X;14) activation of the TCL1 or MTCP1 gene N=25 Hopfinger et al, Cancer 2013, 119: 2258-67

  21. Diseasespecificprofiles (CLL & T-PLL) p = 0.05 p = 0.3365

  22. Diseasespecificprofiles (CLL & T-PLL) p = 0.18 p = 0.0025

  23. Optimizeinput

  24. Summary Wang et al, NEJM 2011, Landau et al, Cell 2013 Unique opportunitymapand understand drugsensitivity (CLL n=100-150; MCL, T-PLL, FL, LPL, Myeloma, B-PLL, Sezary Syndrome n=10-20 each) Cover biologicalheterogeneity & Understand outlier Robust dataforsmaller but significant differences (e.g. BCR-pathway) Clinical translation (incl. trials)

  25. Amsterdam Medical Center • Rien van Oers • Arnon Kater • Paris • Florence Nguyen-Khac • Universität Duisburg/Essen (DKTK) • Marc Seifert • Jan Dürig • Universität Köln • Marco Herling, Natalie Pflug • TU München (DKTK) • Ingo Ringshausen • Universität Freiburg (DKTK) • Katja Zirlik, • Christine Dierks, • Rainer Claus, • Tilmann Brummer • Universität Erlangen • Dimitrios Mougiakakos • Mannheimer Onkologie Praxis • Manfred Hensel Wu Bian Carolin Blume • Jennifer Hüllein Alexander Jethwa Xiyang Liu Olaf Merkel Carolin Muley • Leopold Sellner Tatjana Stolz Mikolaj Slabicki • Stefan Fröhling • Manfred Schmidt Hanno Glimm Christof von Kalle • Sascha Dietrich • Marc Raab • Peter Dreger • Anthony Ho • Anna Jauch • MindaugasAndrulis • EMBL • Wolfgang Huber • MałgorzataOleś • Axel Benner • Benedikt Brors • Peter Lichter • Daniel Mertens • Chris Oakes • Christoph Plass • Martin Sill • Martina Seiffert • Stephan Wolf • Marc Zapatka Deutsche Krebshilfe; Jose-Carreras Leukämiehilfe, Huppert Stiftung; MDACC-DKFZ SINF; HIPO-POP; Helmholtz Virtual Institute; DKTK; German-Israeli Foundation (GIF);

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