Abstract ID 1773203 THE POTENTIAL BENEFITS AND CAVEATS

Abstract ID: 1773203 THE POTENTIAL BENEFITS AND CAVEATS OF PARP INHIBITORS IN EWING SARCOMA Hayriye Verda Erkızan, Ph. D Lombardi Comprehensive Cancer Center Georgetown University, Washington DC Nov CTOS Meeting 12013 Saturday 7. 45 AM 2 nd,

EWS-FLI 1 Protein Partners are Critical for its Function Erkizan, Clinical Cancer Research 2010 79 4 -2 YK- 1 EWS-FLI RHA Erkizan, Nature Medicine 2009 2

EWS-FLI 1 interacts with PARP 1 and other PARP paralogs 3 P R 1 P AR PA P 2 P R PA EWS-FLI 1 IP: 75 k. Da I 1 L F PA 1 P R PA 2 P R PA 3 P R RHA A H R Ig. G L C T EWS-FLI 1 3

YK-4 -279 dissociates PARP 1 from EWS-FLI 1 IP: PARP 1 YK-4 -279 (m. M) 0 1 3 10 WB PARP 1 EWS-FLI 1 Total Cell Lysate EWS-FLI 1 4

PARP inhibitors to overcome other PARP paralogs’ effect 3 P R PA 1 P AR P YK-4 -279 PA 2 P R RHA EWS-FLI 1 5

PARP 16 PARP 15 PARP 14 PARP 13 PARP 12 PARP 10 PARP 4 PARP 9 PARP 3 PARP 2 PARP 1 TNKS 2 TNKS 1 PARP Inhibitors are in Clinical Trials: Not All Are Equal Rucaparib Olaparib Veliparib BMN 673 Niraparib A 966492 0 Not Determined Strong to weak binding Wahlberg, Nat Biotech, 2012 6

Some PARPi selectivity towards PARP 1 in Ewing Sarcoma cells SKES sh. RNA-Luc sh. RNA-PARP 1 k. Da 7

Selective cytotoxicity of PARP 1 i IC 50 Agent SKES sh. PARP 1 Fold difference BMN 673 (m. M) 0. 011 0. 78 71 Olaparib (m. M) 0. 62 13. 8 22. 3 Rucaparib (m. M) 2. 4 15. 03 6. 3 Niraparib (m. M) 3. 5 14. 4 4. 1 A 966492 (m. M) 11. 7 28. 9 2. 5 AG-14361 (m. M) 27. 3 21. 5 0. 8 8

PARPi and Drug interactions 9

PARPi and Drug interactions 10

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

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

Thanks to Dr. Jeff Toretsky/Üren Lab Georgetown University Lombardi Comprehensive Cancer Center Aykut Üren, MD Haydar Çelik, Ph. D Garrett Graham, BS Jenny Han, BS Sung-Hyeok Hong, DVM, Ph. D Tsion Minas, MS Said Rahim, BS Yasemin Saygideger, MD Kamal Sajwan, MS Jeff Schneider, BS Saravana Selvanathan, Ph. D Manisha Taya, MS 13