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A sequential therapeutic strategy of senescence induction and senolytics for elimination of surviving residual breast tumor cells

Award Number: R01CA260819
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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A sequential therapeutic strategy of senescence induction and senolytics for elimination of surviving residual breast tumor cells - Abstract/Summary Chemotherapy and radiation can induce breast tumors to enter a prolonged state of growth arrest with characteristics of senescence. A senescent-like state is also characteristic of residual tumor cells that survive after chemotherapy and/or radiation have eliminated the bulk of a tumor cell population. Tumor cells surviving therapy-induced senescence have the capacity to recover proliferative capacity subsequent to their prolonged growth arrest. Recovery and re-emergence of tumor cells from this growth-arrested state could contribute to disease recurrence months or years after the patient has apparently been cured of the primary disease. Several agents have recently been identified as having senolytic properties [e.g. ABT-263 (navitoclax)] which can selectively kill senescent cells. Given that disease recurrence and consequent cancer mortality is frequently associated with the re-emergence of proliferative tumor cells either at the primary disease site or metastatic sites, a primary goal of this project will be to test the hypothesis that senolytic agents can eliminate therapy induced senescent breast tumor cells to prevent, or at least significantly suppress, cancer recurrence. Aim 1 will examine the hypothesis that the senolytic agent, ABT-263, can efficiently eliminate cells induced into senescence by chemotherapy or radiation when used sequentially (and potentially, repeatedly) after the initial therapy. Sensitivity to senolytics will be assessed in senescence-sorted breast tumor cells, prior to senescence and during the course of recovery, and in residual populations surviving after the bulk of the tumor population has been eliminated by therapeutic agents. The effectiveness of a sequential treatment schedule will also be assessed in vivo using xenograft and PDX tumor models. Aim 2 will interrogate the mechanisms whereby the senolytic ABT-263 promotes cell death in senescent breast tumor cells, with a focus on the contributions of pro- and anti-apoptotic BCL-2 family proteins. Aim 3 will examine the immune response to therapy-induced senescent cells alone and after treatment with senolytics. A phenotypic assessment of tumor infiltrating immune cells and studies with selective immune cell depletion in mouse models will define the nature (adaptive and innate) of the antitumor immune response. Ex vivo studies will further determine NK- and T cell-mediated lysis of senescent cells in the absence or presence of ABT-263. The ability of senolytics to induce immunogenic cell death will be a focus. Toxicity to the host will be compared for exposure to senolytics concomitant with chemotherapy (i.e. prior to entry into senescence) and subsequent to induction of senescence.


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 = $517,388 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	001	5	5/1/2025	NON-COMPETING CONTINUATION	$0
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	002	5	5/22/2025	NON-COMPETING CONTINUATION	$51,739
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	000	5	3/3/2025	NON-COMPETING CONTINUATION	$465,649
2025	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	003	4	6/16/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $517,388

Issue Date FY: 2024 ( Subtotal = $537,452 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	000	4	2/23/2024	NON-COMPETING CONTINUATION	$465,649
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	002	4	4/17/2024	NON-COMPETING CONTINUATION	$25,870
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	001	4	2/27/2024	SUPPLEMENT FOR EXPANSION	$43,515
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	003	4	4/17/2024	SUPPLEMENT FOR EXPANSION	$2,418
														Subtotal = $537,452

Issue Date FY: 2023 ( Subtotal = $543,083 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	001	3	9/21/2023	SUPPLEMENT FOR EXPANSION	$43,892
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	000	3	5/29/2023	NON-COMPETING CONTINUATION	$499,191
														Subtotal = $543,083

Issue Date FY: 2022 ( Subtotal = $499,191 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	000	2	3/1/2022	NON-COMPETING CONTINUATION	$458,437
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	001	2	5/11/2022	NON-COMPETING CONTINUATION	$40,754
														Subtotal = $499,191

Issue Date FY: 2021 ( Subtotal = $509,377 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	000	1	2/26/2021	NEW	$422,784
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	001	1	3/10/2021	NEW	$86,593
														Subtotal = $509,377

Grand Total All Awards = $2,606,491

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A sequential therapeutic strategy of senescence induction and senolytics for elimination of surviving residual breast tumor cells

Award Number: R01CA260819

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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