Novel DNA damage response inhibitor and alkylator combinations for GBM

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PROJECT DESCRIPTION/ABSTRACT – PROJECT 1 Alkylating chemotherapies are part of the backbone of standard-of-care therapy in newly diagnosed disease, and they are also used in the recurrent setting. We and others have demonstrated that these agents each induce unique spectra of DNA damage, which engage specific DNA damage response (DDR) pathways depending on the status of key DNA repair pathways. The most commonly used agents are temozolomide (TMZ), a monofunctional alkylator that induces methyl-adducts on discrete DNA base sites, and lomustine and carmustine, which are bifunctional alkylators that induce both mono-adducts and DNA cross-links. The different DNA lesions induced by these and other alkylating therapies trigger distinct DNA damage responses critically modulated by ataxia-telangiectasia mutated (ATM) and ATM/Rad3-related (ATR) kinases, which orchestrate the cellular response to a broad array of genotoxic insults. Over the past few years, we have collaborated with the NCI Cancer Therapy Evaluation Program and multiple pharmaceutical companies (AstraZeneca, Vertex, Merck KGaA, Bayer) to evaluate multiple highly brain penetrant ATM and ATR inhibitors in combination with radiation therapy and alkylating chemotherapies. Our preliminary data demonstrate robust synergy between TMZ and ATR inhibitors, specifically in GBM models lacking. Mechanistically, unrepaired O6-methyguanine lesions induced by TMZ cause replication stress and activation of the ATR signaling axis. In contrast, synergistic interactions of ATR inhibitors with lomustine were independent of MGMT status, which reflects a distinct set of alkylation lesions that are relatively unaffected by MGMT repair activity. Overall, our extensive preliminary data support the fundamental scientific premise that monofunctional and bifunctional alkylator therapies trigger distinct functional and temporal activation of DNA damage response pathways governed by ATM and ATR. Understanding these relationships can be used to define optimal combinations of ATR or ATM inhibitors with various alkylating agents for GBM.