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Hayriye Verda Erkızan, PhD Lombardi Comprehensive Cancer Center Georgetown University,

Abstract ID: 1773203. THE POTENTIAL BENEFITS AND CAVEATS OF PARP INHIBITORS IN EWING SARCOMA. Hayriye Verda Erkızan, PhD Lombardi Comprehensive Cancer Center Georgetown University, Washington DC. CTOS Meeting 2013 Nov 2 nd , Saturday 7.45 AM. EWS-FLI1 Protein Partners are

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Hayriye Verda Erkızan, PhD Lombardi Comprehensive Cancer Center Georgetown University,

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  1. Abstract ID: 1773203 THE POTENTIAL BENEFITS AND CAVEATS OF PARP INHIBITORS IN EWING SARCOMA Hayriye Verda Erkızan, PhD Lombardi Comprehensive Cancer Center Georgetown University, Washington DC CTOS Meeting 2013 Nov 2nd, Saturday 7.45 AM

  2. EWS-FLI1 Protein Partners are Critical for its Function Erkizan, Clinical Cancer Research 2010 YK-4-279 RHA EWS-FLI1 Erkizan, Nature Medicine 2009

  3. EWS-FLI1 interacts with PARP1 and other PARP paralogs PARP3 PARP1 PARP2 EWS-FLI1 RHA PARP1 PARP2 PARP3 RHA FLI1 TCL IgG IP: 75kDa EWS-FLI1

  4. YK-4-279 dissociates PARP1 from EWS-FLI1 IP: PARP1 WB YK-4-279 (mM) 0 1 3 10 PARP1 EWS-FLI1 Total Cell Lysate EWS-FLI1

  5. PARP inhibitors to overcome other PARP paralogs’ effect PARP1 PARP3 RHA PARP2 EWS-FLI1 YK-4-279

  6. PARP Inhibitors are in Clinical Trials: Not All Are Equal PARP10 PARP12 PARP13 PARP14 PARP15 PARP16 TNKS1 TNKS2 PARP1 PARP2 PARP3 PARP4 PARP9 Rucaparib Olaparib Veliparib BMN673 Niraparib A966492 Not Determined 0 Wahlberg, Nat Biotech, 2012 Strong to weak binding

  7. Some PARPi selectivity towards PARP1 in Ewing Sarcoma cells SKES shRNA-PARP1 shRNA-Luc kDa

  8. Selective cytotoxicity of PARP1i

  9. PARPi and Drug interactions

  10. PARPi and Drug interactions

  11. PARPi and Drug interactions Synergy Niraparib (MK-4827) Olaparib Additive Antagonism YK-4-279 Vincristine Doxorubicin BMN-673 Rucaparib

  12. Conclusion • PARP inhibitor and chemotherapy interactions are heterogeneous. • Therefore, combinatorial therapies should be advanced cautiously and data-driven.

  13. Thanks to Dr. Jeff Toretsky Georgetown University Lombardi Comprehensive Cancer Center Toretsky/Üren Lab AykutÜren, MD HaydarÇelik, PhD Garrett Graham, BS Jenny Han, BS Sung-Hyeok Hong, DVM, PhD Tsion Minas, MS Said Rahim, BS YaseminSaygideger, MD Kamal Sajwan, MS Jeff Schneider, BS SaravanaSelvanathan, PhD ManishaTaya, MS

  14. Direct Binding (By Surface Plasmon Resonance) 40 RU Increased PARP1 binding EWS-FLI1 concentrations 20 0 Time (sec) Affinity: KD~ 20 nM

  15. BMN Olaparib Rucaparib A966492 AG-14361 Niraparib Veliparib INO-1001 Iniparib

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