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Genomics of drug sensitivity in ( primary ) lymphoma

Genomics of drug sensitivity in ( primary ) lymphoma. Map and identify drug sensitivity in leukemias / lymphoma Guilt by association ( drug – disease - patient ) Synergy , combination and response prediction Trial & clinical care in rare diseases. Strategy.

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Genomics of drug sensitivity in ( primary ) lymphoma

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

  2. 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

  3. 3 different large screens 36 patients „EMBL screen“ Step I 2221 compounds (20 patients) 2792 compounds (16 patients) 2-4 concentrations Step II: CLL 67 compounds 1-2 concentrations Step II: NHL 63 compounds 5 concentrations „IC50 platform“ „pilotscreen“ Planned Mid 2014: EMBL Step II (IC50 screen) 200 patients, 100-300 compounds, 10 concentrations

  4. 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

  5. Identify & Understand Drug Sensitivity MCL Essen T-PLL Frankfurt B-PLL Freiburg MZL Heidelberg Refr. CLL Erlangen LPL München Sezary Treat Understand & validate

  6. Genomicsofdrugsensitivity in (primary) lymphoma

  7. SMART SP1. Systematic identification of drug sensitivity in lymphoproliferative diseases (LPD) Thorsten Zenz, MD; Stefan Fröhling, MD; SP2. Targeting kinases and signaling pathways in LPD Katja Zirlik, MD; Rainer Claus, MD; Christine Dierks, MD; Tilman Brummer, PhD; SP3. Microenvironment-mediated drug resistance Ingo Ringshausen, MD; SP4. Metabolic alterations and their therapeutic exploitation DimitirosMougiakakos, MD; SP5. Cellular origin of B cell LPD and drug sensitivity Marc Seifert, PhD; Jan Dürig, MD; SP6. Biology-based treatment in T-LPD Marco Herling, PhD; Jan Dürig, MD; SP7. Computational biology, bioinformatics and statistical data analysis Wolfgang Huber, PhD; MDC/Charite: S. Mathas (T-NHL); S. Sander (Burkitt); C. Schmidt (B-NHL)

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