National Cancer Institute 5U19CA264362-05

Novel DNA damage response inhibitor and alkylator combinations for GBM

This award funds research on novel combinations of DNA damage response inhibitors and alkylating agents for glioblastoma treatment, focusing on ATM and ATR kinase pathways and their synergy with chemotherapy agents like temozolomide.

Description

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. These agents induce unique spectra of DNA damage, engaging specific DNA damage response (DDR) pathways depending on the status of key DNA repair pathways. The most commonly used agents include temozolomide (TMZ), lomustine, and carmustine. These therapies trigger distinct DNA damage responses modulated by ATM and ATR kinases, which orchestrate cellular responses to genotoxic insults. Collaboration with the NCI Cancer Therapy Evaluation Program and pharmaceutical companies has evaluated highly brain-penetrant ATM and ATR inhibitors in combination with radiation therapy and alkylating chemotherapies. Preliminary data show synergy between TMZ and ATR inhibitors, especially in GBM models lacking MGMT. The data support that monofunctional and bifunctional alkylator therapies activate DNA damage response pathways governed by ATM and ATR differently, which can inform optimal combination therapies for GBM.

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