1

Hayriye Verda Erkızan, PhDLombardi Comprehensive Cancer Center

Georgetown University, Washington DC

THE POTENTIAL BENEFITS AND CAVEATS OF PARP INHIBITORS

IN EWING SARCOMA

Abstract ID: 1773203

CTOS Meeting 2013 Nov 2nd, Saturday 7.45 AM

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EWS-FLI1 Protein Partners areCritical for its Function

Erkizan, Clinical Cancer Research 2010

RHAYK-4-279

EWS-FLI1

Erkizan, Nature Medicine 2009

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EWS-FLI1 interacts with PARP1 and other PARP paralogs

IP: FLI1 PARP1

PARP2 PARP3

RHA IgG

TCL

75kDa EWS-FLI1

RHAEWS-FLI1

PARP1

PARP2PARP3

4

YK-4-279 (mM)

PARP1

EWS-FLI1

IP: PARP1

0 1 3 10 WB

Total Cell Lysate

YK-4-279 dissociates PARP1 from EWS-FLI1

EWS-FLI1

5

RHAEWS-FLI1

PARP1

PARP2PARP3

YK-4-279

PARP inhibitors to overcome other PARP paralogs’ effect

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TNK

S1

TNK

S2

RucaparibOlaparibVeliparib

PAR

P1PA

RP2

PAR

P3

PAR

P13

PAR

P14

PAR

P15

PAR

P16

PAR

P4PA

RP9

PAR

P10

PAR

P12

PARP Inhibitors are in Clinical Trials:Not All Are Equal

Strong to weak bindingWahlberg, Nat Biotech, 2012 0 Not Determined

BMN673NiraparibA966492

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Some PARPi selectivity towards PARP1 in Ewing Sarcoma cells

shRNA-PARP1

SKES

shRNA-Luc

kDa

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IC50

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

A966492 (mM) 11.7 28.9 2.5

AG-14361 (mM) 27.3 21.5 0.8

Selective cytotoxicity of PARP1i

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PARPi and Drug interactions

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PARPi and Drug interactions

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Olaparib

YK-4-279 Vincristine

Rucaparib BMN-673

Synergy

Antagonism

Niraparib(MK-4827)

Additive

Doxorubicin

PARPi and Drug interactions

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Conclusion

• PARP inhibitor and chemotherapy interactions are heterogeneous.

• Therefore, combinatorial therapies should be advanced cautiously and data-driven.

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Toretsky/Üren Lab

Dr. Jeff Toretsky

Aykut Üren, MDHaydar Çelik, PhDGarrett Graham, BSJenny Han, BSSung-Hyeok Hong, DVM, PhDTsion Minas, MSSaid Rahim, BSYasemin Saygideger, MDKamal Sajwan, MSJeff Schneider, BSSaravana Selvanathan, PhDManisha Taya, MS

Georgetown UniversityLombardi Comprehensive Cancer Center

Thanks to

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15

40

20

0

RU

Time (sec)

Direct Binding (By Surface Plasmon Resonance)

Affinity: KD~ 20 nM

EWS-FLI1 concentrations

Increased PARP1 binding

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BMN Olaparib

Veliparib

Rucaparib

Iniparib

AG-14361 A966492

INO-1001

Niraparib