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Determining the Immunological Consequences of DNA Replication Stress Response Defects in Renal Cells Carcinoma to Improve Immunotherapy Outcomes

Award Number: R00CA240689
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/03/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Determining the Immunological Consequences of DNA Replication Stress Response Defects in Renal Cells Carcinoma to Improve Immunotherapy Outcomes - PROJECT SUMMARY/ABSTRACT While immunotherapy has shown great promise for robust clinical responses in renal cell carcinoma (RCC), only 1 in 3 patients will see benefit. Current clinical biomarkers, such as mutation burden or PD-L1 expression, have proven to have no predictive capacity in RCC; however, the applicant has recently identified a gene signature of DNA replication stress response (RSR) defects that has predicted immunotherapy response in multiple independent cohorts. This proposal will test the central hypothesis that RSR defects lead to activation of STING signaling to promote sensitivity to immune checkpoint blockade, and that pharmacological induction of RSR defects can sensitize otherwise resistant tumors to immunotherapy. During the K99 mentored phase, the applicant will use highly multiplexed imaging mass cytometry to analyze differences in the immune microenvironment between RSRD-low and RSRD-high patients (Aim 1.1). The applicant will then generated a diverse array of genetically engineered RCC mouse transplant models to enable controlled in vivo studies, and validate that RSR defects are causally linked to immunotherapy response (Aim 1.2). In Aim 2, the applicant will seek to mechanistically understand how RSR defects contribute to immunotherapy response by CRISPR- mediated deletion of STING from an RSRD-high model (Aim 2.1) and in vivo CRISPR screens targeting genes contained within the RSRD signature to ascertain causality (Aim 2.2). The applicant will transition to the R00 independent phase as the CRISPR screen is completed. The CRISPR screen results can serve as a basis for a first R01 submission. Aim 3 will seek to identify pharmacological compounds that will induce RSR defects to sensitize otherwise resistant models to immunotherapy, and will serve as the basis for a second R01 application. This proposal brings together an advisory committee of phenomenal researchers with expertise in DNA damage, immuno-oncology, renal cell carcinoma medical oncology, genetically engineered mouse models, and high- throughput screening to bolster the applicant's skillset in these areas. This will be supplemented by coursework in immunology and responsible conduct of research, as well as additional training to prepare the applicant for leading an independent lab. The environment at MD Anderson, including both the researchers and facilities, makes this one of the few locations where this project could be accomplished. Taken together, this proposal will equip the applicant with the tools to launch by career as a tenure-track faculty member while providing critical insight into immunotherapy for treatment of RCC to advance MD Anderson's goal of Making Cancer History.


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 = -$39,606 )
2026	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Research Manpower	000	5	12/11/2025	NON-COMPETING CONTINUATION	-$39,606
														Subtotal = -$39,606

Issue Date FY: 2024 ( Subtotal = $248,999 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Research Manpower	000	5	7/25/2024	NON-COMPETING CONTINUATION	$248,999
														Subtotal = $248,999

Issue Date FY: 2023 ( Subtotal = $288,605 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Research Manpower	001	4	7/25/2023	NON-COMPETING CONTINUATION	$248,999
2023	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Research Manpower	000	3	11/1/2022	EXTENSION WITH OR WITHOUT FUNDS	$39,606
														Subtotal = $288,605

Issue Date FY: 2022 ( Subtotal = $248,999 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Research Manpower	000	3	8/5/2022	EXTENSION WITH OR WITHOUT FUNDS	$248,999
														Subtotal = $248,999

Grand Total All Awards = $746,997

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Determining the Immunological Consequences of DNA Replication Stress Response Defects in Renal Cells Carcinoma to Improve Immunotherapy Outcomes

Award Number: R00CA240689

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/03/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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