Monday, October 13, 2025 10/13/2025

Differential resistance mechanisms to monofunctional vs bifunctional alkylating agents in glioma

Award Number: F32CA261024
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 07/10/2024

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Differential resistance mechanisms to monofunctional vs bifunctional alkylating agents in glioma - Project Summary Resistance to alkylating agents, including monofunctional temozolomide (TMZ) and bifunctional CCNU, remains a major obstacle to improving outcomes for patients with glioma. An important difference between these therapies is that monofunctional alkylators form several types of alkylated nucleotides, while bifunctional alkylators form highly toxic interstrand crosslinks (ICLs). We hypothesize that CCNU and TMZ kill glioma cells through different mechanisms, leading in some instances to different patterns of resistance and independent effects on outcome that may be leveraged for therapeutic benefit. Resistance to both agents can result from expression of the methyl guanine methyl transferase (MGMT) protein. TMZ resistance can also result from mismatch repair deficiency (MMR-d). Resistance to CCNU has not been systematically characterized but involves members of several DNA damage repair (DDR) pathways. We will extend previous work by systematically probing DDR pathways using varied and representative models and state-of-the-art genomic and functional genomic technologies to test the following hypotheses: Aim 1: TMZ resistance via MMR-d predicts sensitivity to CCNU. Our recent work suggests that MMR-d does not cause CCNU resistance. Using isogenic and patient derived models, we will determine which TMZ resistance mechanisms also result in resistance to CCNU and assess changes in mutational signatures after CCNU treatment. We will then use competition assays and barcoding assays to test the hypothesis that the combination of TMZ and CCNU may provide therapeutic benefit over monotherapy in some contexts. Aim 2: Repair proteins that engage CCNU-induced ICLs determine sensitivity to CCNU. We will test the effect of transcriptional activation of genes known to contribute to ICL repair on CCNU resistance. We will then determine if chemical inhibitors of those proteins can improve CCNU efficacy. Finally, we will perform complete genomic characterization of gliomas pre- and post- CCNU treatment to characterize mutational and SV profiles of CCNU resistance as well as the effect of CCNU treatment on genomic instability. This proposal will shed light on differences in resistance to mono- and bi-functional alkylating agents that may be clinically exploitable to improve outcomes for patients with glioma. This training at the Broad Institute and Dana Farber Cancer Institute will provide Dr. Simona Dalin skills of a faculty member, including systematic and genomic techniques, computational analysis of genomic datasets, algorithm development, and DDR biology. She will also mentor students in aspects of the project.


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 = -$31,892 )
2025	2023	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Research Manpower	000	3	5/27/2025	NON-COMPETING CONTINUATION	-$31,892
														Subtotal = -$31,892

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Research Manpower	001	3	2/5/2024	NON-COMPETING CONTINUATION	$0
2024	2022	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Research Manpower	000	2	2/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $74,292 )
2023	2023	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Research Manpower	000	3	3/30/2023	NON-COMPETING CONTINUATION	$74,292
														Subtotal = $74,292

Issue Date FY: 2022 ( Subtotal = $67,582 )
2022	2022	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Research Manpower	000	2	2/11/2022	NON-COMPETING CONTINUATION	$66,390
2022	2022	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Research Manpower	002	2	8/26/2022	NON-COMPETING CONTINUATION	$1
2022	2022	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Research Manpower	001	2	5/18/2022	NON-COMPETING CONTINUATION	$1,191
														Subtotal = $67,582

Issue Date FY: 2021 ( Subtotal = $65,994 )
2021	2021	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Research Manpower	002	1	3/5/2021	NEW	$0
2021	2021	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Research Manpower	001	1	3/5/2021	NEW	$0
2021	2021	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Research Manpower	000	1	3/5/2021	NEW	$65,994
														Subtotal = $65,994

Grand Total All Awards = $175,976

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Differential resistance mechanisms to monofunctional vs bifunctional alkylating agents in glioma

Award Number: F32CA261024

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 07/10/2024

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