1. THE POTENTIAL BENEFITS AND CAVEATS OF PARP INHIBITORS IN EWING SARCOMA
Abstract ID:
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
RHA
EWS-FLI1
PARP1
PARP2
PARP3
IP:
FLI1
PARP1
PARP2
PARP3
RHA
IgG
TCL
75kDa
EWS-FLI1

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

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

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
Wahlberg, Nat Biotech, 2012
Strong to weak binding

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

8. Selective cytotoxicity of PARP1i
Agent
SKES
SKES shPARP1
Fold difference
BMN 673 (mM)
0.011
0.78 71
Olaparib (mM)
0.62
13.8
22.3
Rucaparib (mM)
2.4
15.03
6.3
Niraparib (mM)
3.5
14.4
4.1
A (mM)
11.7
28.9
2.5
AG (mM)
27.3
21.5
0.8

9. PARPi and Drug interactions

10. PARPi and Drug interactions

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

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

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

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

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