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Targeting the HMGB1-TLR5 pathway to prevent senescence-induced metastasis in breast cancer.

Award Number: R03CA269552
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Targeting the HMGB1-TLR5 pathway to prevent senescence-induced metastasis in breast cancer. - ABSTRACT The current standard for treatment of regional breast tumors involves surgery, radiotherapy or chemotherapy. While effective at reducing or even eliminating the primary tumor burden, chemotherapy can paradoxically promote cancer dissemination and metastasis. Understanding the molecular mechanisms that link chemotherapeutic treatment to metastasis in breast cancer is paramount to developing more effective treatments and a durable response. Exposure to genotoxic stress, as elicited upon chemotherapy or radiotherapy, can result in the engagement of a senescence program in both tumor cells and non-transformed neighboring cells. The presence of senescent cells has recently been shown to promote aggressive traits in cancer tumor models, including increased proliferation, enhanced angiogenesis and activation of the epithelial- to-mesenchymal transition (EMT) program. EMT confers migratory and invasive features to cancer cells, which facilitate their mobilization out of primary tumor sites and into circulation, favoring the metastatic process. The secretion by senescent cells of a specific set of proinflammatory cytokines and chemokines, collectively referred to as the SASP, is believed to mediate the detrimental effects of senescence on tumor cells. The overarching goal of this study is to leverage our understanding of the SASP to blunt the emergence of aggressive tumors following genotoxic treatment. Specifically, we have identified the flagellin receptor TLR5 as a potent regulator of senescence-driven IL-6 secretion in an siRNA screen. We independently confirmed these results, and demonstrated that TLR5 depletion blunts senescence-induced expression of diverse SASP factors. Overall, TLR5 represents an ideal potential therapeutic target to prevent the detrimental effects of the SASP in chemotherapy-treated breast cancer patients. We propose here to determine the contribution of TLR5 signaling to genotoxic stress-induced SASP production in breast cancer cells (aim 1), and to test the hypothesis that blocking the TLR5 signaling pathway prevents the emergence of aggressive phenotypes in chemotherapy-treated breast cancer (aim 2). The long-term goal of this project is to uncover the therapeutic potential of targeting TLR5 as an adjuvant strategy to prevent the resurgence of aggressive breast tumor cells following chemotherapy treatment.


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: 2027 ( Subtotal = -$30 )
2027	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	2	10/20/2026	NON-COMPETING CONTINUATION	-$30
														Subtotal = -$30

Issue Date FY: 2024 ( Subtotal = $84,750 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	2	6/27/2024	NON-COMPETING CONTINUATION	$84,750
														Subtotal = $84,750

Issue Date FY: 2023 ( Subtotal = $84,750 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	1	6/29/2023	NEW	$84,750
														Subtotal = $84,750

Grand Total All Awards = $169,470

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Targeting the HMGB1-TLR5 pathway to prevent senescence-induced metastasis in breast cancer.

Award Number: R03CA269552

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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