Glioblastoma (GBM) with current standard of care is almost uniformly fatal disease. Adding temozolomide (TMZ), an oral chemotherapy drug, during and after radiation therapy has improved treatment of newly diagnosed GBM patients. However, due to emergence of resistance to therapy during or after treatment almost all patients suffer with recurrent disease and there is significant need to identify novel strategies to enhance the efficacy of TMZ. Poly ADP ribose polymerase (PARP) enzymes play critical role in repair of TMZ induced DNA damage and multiple preclinical studies have demonstrated excellent TMZ sensitizing effects of PARP inhibitors. While disruption of repair theoretically should sensitize essentially all tumors to TMZ, the effects of PARP inhibitors are heterogeneous across tumor models. Minimal penetration in to the brain and/or excessive toxicity in combination with TMZ preclude use of some of the PARP inhibitors in GBM, the cause of heterogeneity in response and clear understanding of biomarkers to guide optimal use of PARP inhibitors is lacking. We plan to identify strategies to utilize PARP inhibitors to improve the efficacy of TMZ in GBM. Prior studies combining PARP inhibitors with TMZ in GBM lack comprehensive analysis of molecular mechanisms underlining the resistance evolution and the role of PARP in such processes is unclear. To thwart cytotoxic effects cancer cells may process TMZ induced DNA damage by engaging multiple repair mechanisms, PARP being involved in certain DNA repair pathways, inhibition of PARP may only benefit fraction of all GBMs. Therefore, we hypothesize that identifying mechanism(s) of TMZ resistance that depends on PARP activity may help develop predictive biomarkers of response to the combination of TMZ and PARP inhibitors. Our pharmacodynamic studies have previously showed a more robust potentiation of TMZ-induced DNA damage signaling and survival benefit in TMZ-sensitive models while TMZ resistant lines especially the mgmt- expressing tumors lack DNA damage response. We also reported that adequate concentrations of PARP inhibitor veliparib and TMZ required for TMZ-resistant GBM cells in vivo cannot be achieved using a tolerable dosing regimen. Since PARP inhibitors differ in their potency due to varied chromatin trapping capacity and bioavailability, identifying high potency PARP inhibitor with adequate brain penetration may extend therapeutic window for sensitization of tumors with PARP dependent DNA damage response or repair activity. Based on these considerations, our working hypothesis is that identifying a potent PARP inhibitor with excellent brain penetrance may provoke better sensitizing effects in GBM, and that the specific genetic or molecular features associated with TMZ induced DNA damage response or repair can be used as biomarkers to guide optimal use of PARP inhibitors. We plan to study distinct molecular features associated with response to treatment with PARP inhibition in conjunction with TMZ and test a relatively new PARP inhibitor, BGB-290 in established GBM lines and in patient derived GBM xenograft models. Our preliminary studies suggest that PARP inhibition has varied sensitizing effects in GBM cells with different mechanisms of TMZ resistance. Understanding the link between mechanisms of TMZ resistance and the role of PARP in modulating TMZ sensitivity can help development of PARP inhibitors for GBM or other malignancies treated with TMZ. The planned specific aims are: (1) To identify genetic and molecular alterations modulating TMZ sensitivity and response to PARP inhibition in GBM and (2) To evaluate sensitizing effect of potent PARP inhibitor, BGB-290 in GBM xenograft models. The results from this study will shed new insights into the mechanisms of TMZ resistance and will help designing better treatment for GBM patients.
Temozolomide (TMZ) is a critical component of therapy for patients with glioblastoma multiforme (GBM), but the ultimate efficacy of TMZ is limited by inherent or acquired TMZ resistance and almost all patients suffer with recurrent disease. Poly ADP-ribose polymerase (PARP) being an important enzyme involved in DNA repair, inhibitors of PARP are being developed as sensitizing agent to improve TMZ efficacy in GBM. We have identified that mismatch repair (MMR) as a novel modulator of sensitivity to PARP inhibitors, and propose to define the role of MMR and associated molecular mechanisms determining sensitizing effects of PARP inhibitors, and plan to test a newly developed PARP inhibitor BGB-290 in patient derived xenograft models of GBM as sensitizing therapy.
|Kizilbash, Sani H; Gupta, Shiv K; Chang, Kenneth et al. (2017) Restricted Delivery of Talazoparib Across the Blood-Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma. Mol Cancer Ther 16:2735-2746|