Abstract A249: Navitoclax and veliparib yield cytotoxicity with lower doses than used for single agents in women's cancers.

Background: The apoptosis inhibitor Bcl-XL is upregulated in recurrent ovarian (Ov) and breast (Br) cancer(Ca)s. Modest clinical activity with navitoclax, Bcl-2, Bcl-XL inhibitor, was observed in hematologic malignancies, although a significant grade 3/4 thrombocytopenia has been a challenge for the further development of navitoclax. Our phase I/Ib study of olaparib (PARP inhibitor) and carboplatin ([NCT00647062][1]) in Ov and BrCa patients with BRCA1/2 mutation showed a change in Bim and Bcl-2 tissue protein quantities measured before and after 1 cycle correlated with the duration of response (r2=-0.86, p=0.007). We hypothesized combination of PARP inhibitor, veliparib, with navitoclax will yield clinical synergy at doses lower than used for single agents in women's cancers, thus with the potential to minimize the thrombocytopenia. Materials and Method: We have examined cell injury in Ov (SKOV3, OVCAR8) and triple negative breast cancer (MDA-MB231) cell lines. Cell injury was measured with XTT assays. The clinically attainable dosage of navitoclax and veliparib were compared to the IC50 and a physiologically attainable dose was obtained. Protein expression of Bcl-2, Bcl-XL, Mcl-1, an anti-apoptotic protein of the Bcl-2 family, BAG3, a chaperone protein stabilizing and preventing degradation of Mcl-1 were examined using immunoblot to identify potential biomarkers. Results: Veliparib (up to 50uM) had little single agent activity, up to 11% inhibition of control growth in all cell lines; navitoclax also had limited single agent activity in doses attainable clinically, up to 31% inhibition of control growth at 5uM. Concurrent administration of the two agents yielded a dose dependent increase in cell injury in all cell lines (up to 49% inhibition; p<0.05). Protein expression of Bcl-2 and Bcl-XL was reduced by navitoclax and combination of navitoclax and veliparib showed further reduction in all cell lines. Mcl-1 protein expression was reduced by the combination in all cell lines, although BAG3 was reduced by the combination, only in SKOV3. Further analysis of protein expression, drug effects in soft agar density-independent cultures, and survival assays are in progress in other Br and OvCa cell lines. Conclusions: These preliminary results suggest that the combination of PARP inhibition and Bcl2/Bcl-XL neutralization may be cooperative in yielding better results than either agent alone. Further studies are ongoing to complete credentialing this novel drug combination. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A249. Citation Format: Jung-Min Lee, Alyssa Stacy, Minshu Yu, Elise C. Kohn. Navitoclax and veliparib yield cytotoxicity with lower doses than used for single agents in women's cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A249. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00647062&atom=%2Fmolcanther%2F12%2F11_Supplement%2FA249.atom