Abstract 1651: BGB-290, a novel PARP inhibitor with unique brain penetration ability, demonstrated strong synergism with temozolomide in subcutaneous and intracranial xenograft models
2015
Temozolomide (TMZ) is a DNA alkylating agent, used for treating several malignancies, including glioblastoma multiforme (GBM) and small cell lung cancer (SCLC) with brain metastasis. PARP inhibition could potentially enhance the cytotoxicity of TMZ by hindering the base excision repair (BER) pathway. BGB-290 is a potent and selective inhibitor of PARP1 and PARP2, which is currently under clinical investigation in solid tumors. BGB-290 has significant brain penetration, making it attractive for combining with TMZ in treating brain tumors or tumors with brain metastasis. In this study, we evaluated the combination effect of BGB-290 and TMZ in cellular assays and in animal models. The in vitro combination effect of BGB-290 and TMZ was evaluated in 7 SCLC and 8 GBM cell lines. BGB-290 demonstrated strong synergism with TMZ in most of those cells lines, lowering EC50 of TMZ by at least 5-fold in 4 out of 7 SCLC cell lines, and 7 out of 8 GBM cell lines. The in vivo combination activity was explored in H209 SCLC xenograft model. TMZ single agent was quite effective in this model. One cycle of treatment resulted in all animals tumor-free. However, resistance occurred quickly during the second cycle. Combination of BGB-290 and TMZ significantly delayed resistance without additional toxicity. Tumors remained sensitive to the combination treatment after multiple cycles. In order to investigate whether BGB-290 could overcome the TMZ resistance, TMZ-resistant (TR) H209 tumors were generated by treating the H209 tumors with multiple cycles of TMZ in vivo. The derived H209-TR lines remained sensitive to the combination of BGB-290 and TMZ both in vitro and in vivo, suggesting BGB-290/TMZ combo might work in the TMZ-resistant settings. Approximately 50% of SCLC patients have brain metastases at the time of postmortem examination. BGB-290 showed significant brain penetration in C57 mice. The drug exposure in brain vs. that in plasma was close to 20% after oral administration of BGB-290. Mice with established intracranial H209 xenografts were used to further investigate the combination activity of BGB-290 and TMZ on SCLC in brain. PARylation in brain/tumor tissues was well inhibited at 4 hours after single oral administration of 3 mg/kg of BGB-290. Addition of BGB-290 significantly prolonged animal survival compared to TMZ single agent in this intracranial model. In conclusion, BGB-290 demonstrated strong synergism with TMZ in cellular assays and in SCLC subcutaneous and intracranial xenograft models. When combined with TMZ, BGB-290 can overcome the induced TMZ resistance. Its favorable brain penetration ability warrants further evaluation of BGB-290 in combination with TMZ in GBMs as well as in SCLCs with brain metastasis. Citation Format: Zhiyu Tang, Bin Jiang, Zhenyan Shi, Wenfeng Gong, Yong Liu, Xing Wang, Yajuan Gao, Fenglong Yu, Changyou Zhou, Lusong Luo, Min Wei, Lai Wang. BGB-290, a novel PARP inhibitor with unique brain penetration ability, demonstrated strong synergism with temozolomide in subcutaneous and intracranial xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1651. doi:10.1158/1538-7445.AM2015-1651
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