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Elucidating the interplay between H3K27M variants and DNA damage repair in diffuse midline glioma

Award Number: F30CA298742
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Elucidating the interplay between H3K27M variants and DNA damage repair in diffuse midline glioma - Project Summary: Diffuse midline gliomas (DMG) are rare and fatal brain tumors arising in young children. The past 50 years have seen few therapeutic advancements; the only approved therapy for DMGs remains ionizing radiation (IR) therapy. Genomic profiling of DMGs revealed that they are driven by K27M mutations in the genes encoding either the canonical Histone 3 (H3.1) protein or its variant H3.3, core members of the nucleosome complex that regulates genome organization. However, H3K27M mutations are insufficient to drive DMG formation as single alterations and must occur conjuction with secondary alterations. Nearly all DMGs have mutations that inactivate p53, however the mode of inactivation varies between tumors. Additionally, H3.1K27M and H3.3K27M define separate subsets of DMGs, with distinct downstream molecular alterations. Our group showed that H3.3K27M DMGs have frequent TP53 mutations, which completely ablate p53 function, and exhibit significant genomic instability, with frequent and complex structural variants (SVs) – which result from errors double-stranded DNA break (DSB) repair. In contrast, H3.1K27M DMGs are enriched for alterations that partially inhibit p53 and are more genomically stable. The overarching aim of this proposal is to test whether H3.1K27M and H3.3K27M differentially alter p53 activity and promote tolerance of DNA-damage through different mechanisms, and whether this process creates vulnerabilities that can be targeted using novel therapeutic approaches. In Specific Aim 1, I will test whether the differences in genomic stability between H3.1K27M and H3.3K27M DMG subsets are explained by differences in mitotic stability produced by the mutations. I hypothesize that H3.3K27M expression predisposes cells to mitotic errors, resulting in increased rates of DSBs and SV formation in this DMG subset. In Specific Aim 2, I will test whether the high frequency of p53 loss in H3.3K27M DMGs is due to selective pressures induced by H3.3K27M expression. I hypothesize that H3.3K27M expression induces p53 activity and leads to cell cycle blocks. Therefore, cells expressing H3.3K27M would experience a strong selection pressure to inactivate p53, thereby increasing genomic instability in the resulting tumor. In Specific Aim 3, I will test whether p53-reactivation therapy is a viable strategy in DMGs that are wild-type for p53 itself, and will evaluate whether MAPK inhibition synergizes with p53-reactivation to increase the efficacy of therapy and circumvent the development of therapeutic resistance. I hypothesize that p53 reactivation engenders a compensatory dependency on MAPK signaling that can be therapeutically targeted in DMGs. Taken together, these aims will test the overlying hypothesis that H3.3K27M and H3.1K27M lead to differential responses to DNA damage and p53 inactivation. The information generated from these aims will provide a profile of the pressures driving early tumor evolution in DMGs, and may provide potential therapeutic strategies to target p53 or increase the efficacy of existing DSB-generating therapies like ionizing radiation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $55,114 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	2	8/17/2026	NON-COMPETING CONTINUATION	$55,114
														Subtotal = $55,114

Issue Date FY: 2025 ( Subtotal = $42,480 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	1	8/1/2025	NEW	$42,480
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	001	1	8/1/2025	NEW	$0
														Subtotal = $42,480

Grand Total All Awards = $97,594

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Elucidating the interplay between H3K27M variants and DNA damage repair in diffuse midline glioma

Award Number: F30CA298742

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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