Friday, May 3, 2024
5/3/2024
Project Summary Adult diffuse gliomas that harbor mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) are common in younger adults, and universally evade the current aggressive therapies and remain lethal. Our team led by Co-PIs Drs. Cahill and Wakimoto have identified unique metabolic dependencies and combinatorial therapeutic strategies for IDH-mutant glioma. We have found that poly(ADP-ribose) polymerases (PARP) activation induced by the alkylating chemotherapeutic temozolomide can be therapeutically exploited by inhibition of the PAR breakdown enzyme poly(ADP-ribose) glycohydrolase (PARG), resulting in aberrant PAR accumulation and catastrophic NAD+ depletion. In parallel, PARP “trapping” inhibition has been found to be synthetic lethal with IDH1 mutation, exploiting a replication-stress mechanism convergent with BRCA1-mediated homologous-recombination deficiency. However, systemic hematologic toxicities have limited the PARP inhibitor dosing in glioma patients. Therefore, the goal of our R01 application is to dissect the PAR-driven signaling pathways in IDH mutant gliomas, providing a mechanistic understanding in malignant glioma cells of the mediators of sensitivity, to maximize cancer cell targeting and minimize systemic toxicities, ultimately accelerating translation of laboratory discoveries to the clinic. Focal radiation therapy is part of standard care for gliomas and an its enhancement is an unmet need. Radiation also offers the opportunity to overcome the systemic toxicities associated with TMZ-based combination therapies. Aim 1 will determine how radiation therapy-induced DNA damage and PAR-ylation co-operates with PARG inhibition in IDH mutant tumor models in vitro and in vivo. Employing genetic and pharmacological inhibition of PARG, we will determine the therapeutic effects and molecular mechanisms of PARG inhibition in preclinical models of glioma. Mechanistically, PAR signaling activation can drive multiple downstream molecular pathways including NAD+ depletion, replication stress, DNA damage and AIF-MIF-driven parthanatos, all of which can contribute to cell death. Aim 2 will determine whether signaling downstream of PAR polymers directly contributes to cell death after treatment with alkylators and PARG inhibition to understand the molecular basis of the combination of TMZ and PARG inhibition. Our ongoing research has revealed that genotoxicity-triggered aberrant PAR-ylation perturbed DNA replication stress checkpoint signaling in IDH-mutant tumors, motivating us to investigate the ability of potent, selective, clinical DNA-PKcs inhibitors to disable radiation-induced replication stress responses in Aim 3. The successful completion of these specific aims will open new avenues for targeting the specific vulnerabilities of IDH1 mutant gliomas, driving potential clinical therapies for patients with these tumors.
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