Enhancing Temozolomide Efficacy: The Synergistic Role of BGB-290 in Treating Brain Tumors and Metastases

Temozolomide (TMZ) is recognized for its role in treating various cancers such as glioblastoma multiforme and lung cancer with brain metastasis. The integration of PARP inhibition, exemplified by BGB-290, a potent and selective PARP1/2 inhibitor, is being examined for its potential to amplify TMZ's cytotoxic impact by obstructing the base excision repair mechanism. BGB-290's notable capacity to penetrate the brain makes it a promising candidate for combination therapy with TMZ, especially for brain tumors and cancers with metastatic spread to the brain.

Our research assessed the combined impact of BGB-290 and TMZ through cellular and animal model studies. In vitro testing across seven SCLC and eight GBM cell lines showed a significant synergistic effect, with TMZ's EC50 being reduced by at least five times in the majority of the cell lines tested.

In vivo studies using the H209 SCLC xenograft model revealed that while TMZ was initially effective, resistance developed rapidly in subsequent cycles. However, the combination of BGB-290 with TMZ notably postponed the emergence of resistance without increasing toxicity, maintaining tumor sensitivity to the combined treatment over multiple cycles. Furthermore, H209 tumors that had developed resistance to TMZ (H209-TR) were found to remain responsive to the BGB-290 and TMZ combination both in vitro and in vivo.

Given that approximately half of SCLC patients exhibit brain metastases at the time of autopsy, BGB-290's brain penetration was evaluated in C57 mice, showing substantial brain levels relative to plasma levels post-administration. The combination of BGB-290 and TMZ was further investigated in an intracranial H209 xenograft model, where it was found that BGB-290 significantly prolonged survival rates compared to TMZ alone.

The study concludes that BGB-290, when combined with TMZ, not only exhibits strong synergistic effects in cellular assays and SCLC models but also has the potential to counteract TMZ-induced resistance. The drug's favorable brain penetration underscores the need for further research into its combined use with TMZ for treating GBM and SCLC with brain metastasis.