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Synthetic lethalities to cell cycle disruption in glioma

Award Number: R01CA262462
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/13/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Synthetic lethalities to cell cycle disruption in glioma - Summary Despite decades of research into targeted therapeutics against gliomas, the most successful treatments remain DNA damaging agents: radiation and the alkylating agents temozolomide and lomustine. DNA damage generates particular obstacles for rapidly dividing cells; as cells undergoing such damage progress through the cell cycle, they can undergo genotoxic or mitotic catastrophe. Multiple compounds have recently been developed that interfere with cell cycle regulation, with the aim of generating mitotic catastrophe in cancer cells. These include compounds targeting regulators of the G2/M checkpoint, including CHK1 and CHK2; WEE1; and others. Some of these are being applied to gliomas in clinical trials, including a trial of the WEE1 inhibitor AZD1775 in patients with glioblastoma. However, a detailed understanding of which gliomas are most likely to require a functional G2/M checkpoint, and under what conditions, is not available. Therefore, despite this pathway being highly relevant to the most successful existing therapeutics, we do not know when or how to use modulators of the pathway in patients with glioma. The objective of this proposal is to determine whether and in what instances inhibitors of the G2/M checkpoint, and particularly CHK1/2, can lead to improved outcomes in gliomas. We evaluated the effects of 400 biologically active small molecules on 78 glioma cell lines with comprehensive genomic characterization, including conventional and neurosphere lines. One of the most prominent outcomes was that inactivation of TP53 was associated with worse response to almost all compounds, but combined loss of TP53 and CDKN2A/B rendered cells more sensitive to G2/M checkpoint inhibitors, especially inhibitors of CHK1/2 (CHK1/2i). We hypothesize that combined loss of TP53 and other G1/S cell cycle regulators leads to a reliance on the CHK1/2-controlled G2/M checkpoint to avoid uncontrolled cell cycling in the context of genotoxic or replicative stress. By understanding the mechanisms underlying G2/M inhibitor sensitivity, we will have potential for a major near-term impact on treatment through optimized therapeutic strategies using these inhibitors, which are already under development, that can lead to immediate incorporation into new clinical trials strategies. We will achieve this with the following specific aims: Aim 1: Test the hypothesis that combined loss of TP53 and G1/S checkpoint control generates sensitivity to G2/M checkpoint inhibitors. Aim 2: Test the hypothesis that cell differentiation state determines sensitivity to G2/M checkpoint inhibition. Aim 3: Test the hypothesis that MDM2 inhibitors can increase the therapeutic window of CHK1/2i in the context of DNA damaging agents. In summary, the proposal described should lead to better diagnostics and treatments for those afflicted by gliomas and offer new avenues for clinical trial design and implementation in patient studies.


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 = $673,491 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	4	5/8/2025	NON-COMPETING CONTINUATION	$673,491
														Subtotal = $673,491

Issue Date FY: 2024 ( Subtotal = $639,818 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	3	8/12/2024	NON-COMPETING CONTINUATION	$639,818
														Subtotal = $639,818

Issue Date FY: 2023 ( Subtotal = $660,022 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	2	5/10/2023	NON-COMPETING CONTINUATION	$660,022
														Subtotal = $660,022

Issue Date FY: 2022 ( Subtotal = $668,921 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	1	5/13/2022	NEW	$668,921
														Subtotal = $668,921

Grand Total All Awards = $2,642,252

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Synthetic lethalities to cell cycle disruption in glioma

Award Number: R01CA262462

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/13/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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