Mechanistic and Therapeutic Development of ATM as a Tumor Cell Selective Target for Radiosensitization in H3K27M DMG
Radiation is the primary treatment for diffuse midline gliomas (DMGs). Unfortunately, the vast majority of these tumors recur within the radiation treatment field owing to the inherent resistance of these tumors to radiotherapy. Given that radiation kills tumor cells by inducing DNA double strand breaks (DSBs), experimental therapeutics which target the DNA damage response are promising strategies for improving radiation therapy outcomes. In addition, genetic mechanisms unique to tumor cells such as histone 3 K27M (H3K27M) mutation, a defining characteristic of DMG, may represent vulnerabilities which are present in tumor cells but not in normal cells and thus confer tumor cell selectivity to DDR therapeutic approaches. We recently discovered that H3K27M is associated with both increased expression and activity of ATM, a central protein in the cellular response to radiation-induced DNA damage. Furthermore, our preliminary data demonstrate that ATM inhibition by the clinical candidate agent AZD1390 is a potent radiosensitizer in H3K27M mutant but not matched H3K27 wildtype DMG cells.
Project Goal:
The overall goal of this application is to characterize the interactions between H3K27M mutation, ATM and DSB repair to inform the development of a tumor cell selective therapeutic strategy combining the ATM inhibitor AZD1390 and radiotherapy. This goal will be achieved through two specific aims, the first of which will define how H3K27M mutation modifies ATM gene expression through epigenetic mechanisms and regulates DNA repair pathways critical for the repair of radiation-induced DNA damage. The second aim of this proposal will test the therapeutic benefit of AZD1390 in combination with radiation in mouse models of human H3K27M with a focus on tumor efficacy, toxicity, and selectivity of therapy toward tumor cells with H3K27M mutation relative to normal brain. Completion of these aims will support the long-term goal of this application to initiate a clinical trial combining ATM inhibition with standard-of-care radiotherapy in children with DMG.
Project Update 2024:
We have characterized the interactions between H3K27M mutation, ATM expression, and ATM-mediated DNA damage response signaling to inform the development of a tumor cell selective therapeutic strategy combining the ATM inhibitor AZD1390 and radiotherapy. We have discovered that H3K27M mutation modifies ATM gene expression through direct epigenetic mechanisms and resulting in heightened dependency on ATM-mediated DNA damage response signaling that is critical for the repair of radiation-induced DNA damage. Translation of these finding to animals with human H3K27M mutant DMG tumors revealed a therapeutic benefit of AZD1390 in combination with radiation that was tolerable and efficacious, noting that survival was significantly longer in animals treated with the combination of AZD1390 and radiation (versus either agent alone or untreated animals). This work will inform a potential future clinical trial combining AZD1390 with standard-of-care radiotherapy in children with H3K27 mutant DMG.
