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Advancing WRN as a synthetic lethal target for microsatellite unstable cancers

Award Number: K08CA256173
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Advancing WRN as a synthetic lethal target for microsatellite unstable cancers - Project Summary Microsatellite instablility (MSI), a class of genetic hypermutability arising from impaired DNA mismatch repair, contributes to development to types of cancers. While immune checkpoint blockade (ICB) is effective for some patients, 45-60% of patients do not response to ICB and the use of these agents can be limited by their toxicity and/or acquired resistance. The pressing need for further therapies against this large class of cancers inspired our efforts identifying the RecQ helicase WRN as a synthetic lethal target for MSI cancers. This discovery raises fundamental questions about how WRN functions to protect the MSI cancers from DNA double strand breaks and what is the best strategy to implement WRN inhibition to treat MSI cancers. This project seeks to address these questions by first testing our hypothesis that WRN is required to unwind secondary DNA structures that are specifically enriched in MSI cells (Aim 1). Furthermore, we will explore the structure/function relationship of WRN in the context of MSI with a goal of identifying essential regions to inform drug discovery efforts (Aim 2). Our preliminary data also demonstrated that WRN inhibition induces a TNFα transcriptional response in MSI cells. These results inspired our hypothesis that the DNA damage following WRN depletion triggers an innate immune response in MSI cancers (Aim 3). By integrating functional genomics, biochemical techniques, DNA repair biology, and in vivo modeling, we seek to define the mechanism underlying the dependence upon WRN in MSI cells for survival, facilitate rational design of WRN inhibitors, and promote development of new combination therapies for MSI cancers. I am a medical oncologist with a background in functional genomics and DNA repair biology. My long-term goal as a physician-scientist is to lead a basic/translational laboratory studying how cancers tolerate impaired DNA repair pathways and the vulnerabilities that arise in this context. I will be primarily mentored by Dr. Adam Bass at the Broad Institute and Dana-Farber Cancer Institute. Furthermore, my scientific advisory committee composed of Drs. Alan D’Andrea, Raymond Monnat, Matthew Meyerson, and David Barbie will help guide my scientific and career development. Coupled with collaborations with Drs. Andre Nussenzweig and Tyler Jacks, a focused training and career developmental plan, the proposed training plan will help me build the momentum to launch my career as an independent investigator.


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: 2024 ( Subtotal = $238,634 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Research Manpower	000	4	8/13/2024	NON-COMPETING CONTINUATION	$238,634
														Subtotal = $238,634

Issue Date FY: 2023 ( Subtotal = $238,634 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Research Manpower	003	3	8/8/2023	NON-COMPETING CONTINUATION	$238,634
2023	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Research Manpower	000	2	2/24/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2022	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Research Manpower	002	2	4/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$15,492
2023	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	001	1	4/25/2023	NEW	-$15,492
														Subtotal = $238,634

Issue Date FY: 2022 ( Subtotal = $238,634 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Research Manpower	001	2	9/3/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$238,634
2022	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	1	9/3/2022	NEW	$0
														Subtotal = $238,634

Issue Date FY: 2021 ( Subtotal = $237,994 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	1	7/21/2021	NEW	$237,994
														Subtotal = $237,994

Grand Total All Awards = $953,896

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Advancing WRN as a synthetic lethal target for microsatellite unstable cancers

Award Number: K08CA256173

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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