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Genome-based prediction of drug effects in chronic lymphocytic leukemia

Genome-based prediction of drug effects in chronic lymphocytic leukemia. Gosia Oleś 5 th September 2013 Group Retreat. Projects. shRNA screen in CLL Collaboration with: Mikołaj Słabicki , Thorsten Zenz , NCT shRNA Screens in Primary Colon Cancer Spheroids

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Genome-based prediction of drug effects in chronic lymphocytic leukemia

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  1. Genome-based prediction of drug effects in chronic lymphocytic leukemia Gosia Oleś 5th September 2013 Group Retreat

  2. Projects • shRNA screen in CLL • Collaboration with: MikołajSłabicki, Thorsten Zenz, NCT • shRNA Screens in Primary Colon Cancer Spheroids • Collaboration with: TaronishDubash, Hanno Glimm, NCT • Whichfactorsinfluencetheselfrenewalcapacityoftumorinitiatingcells? • Chronic lymphocytic leukemia • Collaboration with Leopold Sellner, Thorsten Zenz, NCT

  3. Projects • shRNA screen in CLL • Collaboration with: MikołajSłabicki, Thorsten Zenz, NCT • shRNA Screens in Primary Colon Cancer Spheroids • Collaboration with: TaronishDubash, Hanno Glimm, NCT • Whichfactorsinfluencetheselfrenewalcapacityoftumorinitiatingcells? • Chronic lymphocytic leukemia • Collaboration with Leopold Sellner, Thorsten Zenz, NCT

  4. shRNA Screens in Primary Colon Cancer Spheroids TSC01/TSC03 Metastatizing / Non-Metastatizing SphereCulture Negative shRNA In vitro screen Direct In vivo Screen PositiveshRNA In vitro to In vivo screen 2d Recovery TSC01& TSC03 TSC01 TSC01& TSC03 Transduction Pooledinfection onevirus per cell

  5. Projects • shRNA screen in CLL • Collaboration with: MikołajSłabicki, Thorsten Zenz, NCT • shRNA Screens in Primary Colon Cancer Spheroids • Collaboration with: TaronishDubash, Hanno Glimm, NCT • Whichfactorsinfluencetheselfrenewalcapacityoftumorinitiatingcells? • Chronic lymphocytic leukemia • Collaboration with Leopold Sellner, Thorsten Zenz, NCT

  6. Chronic lymphocytic leukemiaproject • Primary drug screen • 97 patients • 67 drugs • 5 gene mutations (BRAF, MYD88, NOTCH1, SF3B1, TP53) and 7 chromosomal rearrangements (6q21, 8q24, 11q22.3, 12q13, 13q14, 17p13, 18q21) Primary cancer cells derived from patients • 2. EMBL drug screen • 10 patients • 1120 compounds • 3. Synergy screen • The primary drug screen + BTK inhibitor • 3. WES • 91 patients

  7. day2 vs. day3

  8. Drug clustering inuence on p53-mediated pathways Fludarabine 1µM, 10µM Nutlin-3 10µM

  9. Drug clustering inuence on p53-mediated pathways Fludarabine 1µM, 10µM Nutlin-3 10µM inhibitors of mammalian target of rapamycin (mTOR) Everolimus (RAD001) 1µM, 10µM Deforolimus 1µM, 10µM

  10. Drug clustering inuence on p53-mediated pathways Fludarabine 1µM, 10µM Nutlin-3 10µM inhibitors of mammalian target of rapamycin (mTOR) Everolimus (RAD001) 1µM, 10µM Deforolimus 1µM, 10µM MK-1775 10µM PCI-32765 1µM CAL-101 1µM, 10µM kinesin inhibitors

  11. Specific genotype-drug interaction • TP53 • Nutlin-3 • Fludarabine • 11q22 deletion • Rotenone – insecticide, piscicide • Dasatinib– multi-BCR/ABL and Src family tyrosine kinase inhibitor • KU-60019 – ataxia telangiectasia (A-T) mutated (ATM) kinase inhibitor • PCI−32765 – Bruton’s tyrosine kinase (BTK) inhibitor • AZD7762 – ATP-competitive checkpoint kinase inhibitor • SGI−1776 free base – ATP competitive inhibitor to Pim kinases • NVP−TAE684 – anaplastic lymphoma kinase (ALK) inhibitor • AT13387 – heat shock protein 90 (Hsp90) inhibitor

  12. day2: 11q22.3 deletion

  13. Synergy screen • Bruton’s tyrosine kinase inhibitor (Ibrutinib) • critical signaling kinase in the B-cell receptor pathway for tumor cell survival and proliferation • treatment for various B-cell malignancies

  14. EMBL screen - Prestwick library P0021 P0369 P0043 EMBL Run I Nutlin and Fludarabine sensitivity reproducible NCT screen Inhibition

  15. Our data vs. other data sets Viability [% of control] TP53 mut TP53 wt ln (IC_50 [μM]) Garnett et al. , Nature 2012 TP53 mut TP53 wt

  16. Future plans • Define genetic background of every patient from the WES data • Correlate the genetic information with the diverse response profiles • Select compounds for next synergy screens

  17. Acknowledgements • Huber Group Wolfgang Huber Simon Anders Joseph Barry Bernd Fischer Julian Gehring Bernd Klaus Felix Klein Andrzej Oleś Aleksandra Pękowska Paul Pyl Alejandro Reyes Maria Secrier Jan Swedlow • LeoplodSellner • Thorsten Zenz • MikołajSłabicki • TaronishDubash • Hanno Glimm

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