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Replication stress response defects predict and enhance immune checkpoint therapy response in triple negative breast cancer

Award Number: R01CA247862
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Replication stress response defects predict and enhance immune checkpoint therapy response in triple negative breast cancer - Project Summary The lack of specific targets for the treatment of triple-negative breast cancer (TNBC) is a major challenge, as many TNBCs do not respond to cytotoxic chemotherapies. Immune checkpoint blockade (ICB) has yielded promising results in both advanced and early-stage TNBC and is expected to substantially improve the overall prognosis of patients with this disease. However, since TNBC is not inherently immunogenic, it is important to identify patients who would benefit most from immunotherapy and to identify agents that can prime the tumor microenvironment to enhance the therapeutic effects. TNBC is known to exhibit high levels of replication stress, which occurs when the DNA replication machinery encounters obstacles that impede the replication process. In normal cells, replication stress activates the replication stress response (RSR) to maintain genome integrity. Defective RSR allows cells with high replication stress to survive and proliferate. Recently, we have identified a gene signature that represents defects in RSR (RSRD). We found this RSRD signature to be highly enriched in TNBC cells. Furthermore, RSRD-high TNBC cells accumulate cytoplasmic DNA and induce STING-dependent cytokine production, which is required for the effectiveness of ICB. Intriguingly, the RSRD signature score correlates perfectly with the response of TNBC to ICB in syngeneic mouse models, and it accurately predicts ICB response across 5 low–mutation-burden tumor lineages. All these intriguing findings support the hypotheses that RSRD may act as a key determinant of ICB outcomes in low–mutation-burden cancers, including TNBC, and that RSRD-enhancing drugs may sensitize ICB-resistant TNBC to immunotherapy. These hypotheses will be tested via 3 specific aims. (1) To determine how the immune microenvironment is modified in RSR-defective TNBC. We will use a highly multiplexed imaging mass cytometry panel to determine how RSRD remodels the immune microenvironment of TNBC and induces susceptibility to ICB. In addition, we will manipulate the RSR status in TNBC cells to assess the relationship between RSR defects and immunotherapy response. (2) To identify causative drivers of RSRD-high–mediated ICB responsiveness in TNBC. Our preliminary studies suggest that RSR defects may drive immunotherapy response through accumulation of immunostimulatory cytosolic single-stranded DNA (ssDNA). We will, therefore, seek to manipulate the cytosolic ssDNA level in TNBC models to determine whether cytosolic ssDNA is indeed a causative driver of ICB responsiveness in TNBC. In addition, to understand why our RSRD gene signature predicts response to ICB in TNBC, we will apply an in vivo CRISPR screen to determine what transcriptional changes contained within our RSRD gene signature cause this response. (3) To develop novel combination therapy to convert RSRD-low TNBC to RSRD-high to improve their response to ICB. Using cutting-edge systems and bioinformatics approaches, we have identified many potential RSRD-inducing agents. We will assess the 6 most promising candidates and identify the best candidate compound that can effectively sensitize RSRD-low TNBC to ICB.


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 = $332,463 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	12/27/2024	NON-COMPETING CONTINUATION	$332,463
														Subtotal = $332,463

Issue Date FY: 2024 ( Subtotal = $350,935 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$18,472
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	4	1/5/2024	NON-COMPETING CONTINUATION	$332,463
														Subtotal = $350,935

Issue Date FY: 2023 ( Subtotal = $362,016 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	1/27/2023	NON-COMPETING CONTINUATION	$362,016
														Subtotal = $362,016

Issue Date FY: 2022 ( Subtotal = $362,016 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	2	5/24/2022	NON-COMPETING CONTINUATION	$29,553
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	1/26/2022	NON-COMPETING CONTINUATION	$332,463
														Subtotal = $362,016

Issue Date FY: 2021 ( Subtotal = $369,404 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	1/19/2021	NEW	$369,404
														Subtotal = $369,404

Grand Total All Awards = $1,776,834

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Replication stress response defects predict and enhance immune checkpoint therapy response in triple negative breast cancer

Award Number: R01CA247862

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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