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Enhanced radiotherapy for pediatric glioma via synthetic lethal vulnerabilities

Award Number: R01CA284565
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Enhanced radiotherapy for pediatric glioma via synthetic lethal vulnerabilities - Project Summary Diffuse midline gliomas (DMG) are the most common malignant brain tumors of children. They are surgically inaccessible and refractive to chemotherapy. The prevalent oncogenic driver--an H3K27M mutation of histone H3--is undruggable. Radiotherapy is the standard of care for DMG, and the only treatment that prolongs patient survival. However, H3K27M DMGs inevitably recur following radiotherapy and are uniformly fatal. Against this backdrop, we propose this R01 response to PAR-22-198 from the NCI entitled “Precision Approaches in Radiation Synthetic combinations (PAIRS).” Our broad goal is to improve survival of children with DMG. The point of departure for our study plan is a recently completed genome-wide CRISPR screen aimed at identifying DMG-specific vulnerabilities. Our screen identified a conditional synthetic lethality at the junction of replication stress (RS) and the consequent DNA damage response (DDR). This vulnerability is druggable and has potential to enhance the efficacy of radiotherapy in DMG synergistically--a strategy specifically proposed by PAIRS. Our testable hypothesis is that a sustainable balance between RS and DDR in DMGs can be tipped to therapeutic advantage by combining radiation and ATR antagonists (which increase RS) or by radiation plus inhibitors of DNA polymerase Q (which decrease DDR). In collaboration with a corporate partner, we have identified clinical-stage, brain-penetrant antagonists of ATR and POLQ. For clinical trials we are an integral member of the international Pacific Pediatric Neuro- Oncology Consortium (PNOC). Drawing upon these resources, our aims are to test three specific predictions of our hypothesis. Aim 1 (target specificity) tests the prediction that synergistic killing of DMG cells by the combination of radiation plus ATR or POLQ antagonist reflects “on target” responses to enhanced RS or suppressed DDR (induced by ATR or POLQ antagonist, respectively). Aim 2 (chromatin structure) tests the prediction that the H3K27M driven altered chromatin propels dependency on ATR and POLQ. Aim 3 (therapeutic potential) tests the predictions that (a) the variability in DMG patient responses to radiotherapy reflects patient-specific differences in the pre-therapeutic burden of DDR and RS and (b) that markers of RS and DDR will correlate with response to therapy in “avatar clinical trials” with patient-derived xenografts of DMGs. The study plan is enabled by an interactive collaboration among three investigators whose skill sets exceed the sum of their parts. Daphne Haas-Kogan, M.D. is a clinician-scientist with much practical experience in the clinical care of children with DMG. As Chair of Radiation Oncology at Dana-Farber Cancer Institute, DHK interacts frequently with Dipanjan Chowdhury, Ph.D. - a DNA enzymologist with deep expertise in DNA replication and repair. In clinical studies proposed for Aim 3, DHK and DC will work closely with Sabine Mueller, M.D. - an expert on the design and conduct of clinical trials and leader of the PNOC consortium.


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: 2025 ( Subtotal = $1,161,942 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	001	2	6/12/2025	NON-COMPETING CONTINUATION	$870,926
2025	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	1	12/23/2024	NEW	$291,016
														Subtotal = $1,161,942

Issue Date FY: 2024 ( Subtotal = $475,993 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	1	9/3/2024	NEW	$475,993
														Subtotal = $475,993

Grand Total All Awards = $1,637,935

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Enhanced radiotherapy for pediatric glioma via synthetic lethal vulnerabilities

Award Number: R01CA284565

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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