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Bladder cancer PD-L1 control of homologous recombination: Basic mechanisms applied to novel treatments

Award Number: R01CA268641
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Bladder cancer PD-L1 control of homologous recombination: Basic mechanisms applied to novel treatments - This revised MPI proposal assembles experts in bladder cancer, tumor biology, DNA damage response (DDR) and pre-clinical models with a long-standing history of productive collaborations to study effects of intracellular bladder cancer PD-L1 signals on BRCA1-mediated DDR, and how such signals alter sensitivity to PARP inhibitors and immune checkpoint blockade immunotherapy in orthotopic/metastatic mouse and human models. We test transplantable mouse bladder cancer lines MB49 and MBT-2, and the human bladder cancer lines RT4, UM-UC3 and UM-UC14, representing basal and luminal histologies plus new PDX, xenograft and organoid models and our novel GEMM all per reviewer request . Intracellular PD-L1 signals are interrogated using control versus genetically manipulated tumors and other approaches including new non-biochemical approaches per reviewer request . We will use these clinically relevant models together to test our overarching hypothesis that bladder cancer PD-L1 signals promote the homologous recombination DDR pathway that suppresses PARP inhibitor and immune checkpoint blockade immunotherapy efficacy. Aim 1: Define mechanisms for PD-L1-mediated control of HR. We will use well-validated genetic, biochemical and pharmacologic approaches plus definitive cell reporter assays for homologous recombination, RNA-seq, proteomics, RPPA, immunoblots, CRISPR library screens, organoids and digital imaging with image analysis software to understand how PD-L1 regulates BRCA1 functionality and to test mechanisms, including for tumor immunogenicity. We identified FDA-approved pharmacologic agents that we repurposed to deplete tumor PD-L1 and inhibit HR, for which we define mechanisms. Aim 2: Define treatment consequences of PD-L1 controlled homologous recombination/BRCA1 effects. Control versus genetically PD-L1 depleted cells with genetic perturbations of BRCA1 and related molecules will be tested for in vivo effects by challenging engineered cells into mice and treating with single agents or combinations, based on findings from Aim 1 to assess treatment efficacy and specific mechanisms. We use transplantable, syngeneic mouse models, and human xenograft and humanized mouse models in which we have extensive experience. Notably, we will assess tumor microenvironmental and immune contributions to treatments using genetically immune altered mice, adoptive cell transfers and immune blocking/neutralizing molecules. In vivo data are mechanistically refined in in vitro assays in which we are expert. PDX, organoids


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 = $633,409 )
2025	2025	DARTMOUTH-HITCHCOCK CLINIC	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Cancer Treatment Research	000	3	8/8/2025	NON-COMPETING CONTINUATION	$633,409
														Subtotal = $633,409

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	DARTMOUTH-HITCHCOCK CLINIC	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Cancer Treatment Research	000	2	9/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $620,740 )
2023	2023	DARTMOUTH-HITCHCOCK CLINIC	ONE MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Cancer Treatment Research	000	2	8/21/2023	NON-COMPETING CONTINUATION	$620,740
														Subtotal = $620,740

Issue Date FY: 2022 ( Subtotal = $646,659 )
2022	2022	DARTMOUTH-HITCHCOCK CLINIC	ONE MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Cancer Treatment Research	000	1	8/22/2022	NEW	$646,659
														Subtotal = $646,659

Grand Total All Awards = $1,900,808

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Bladder cancer PD-L1 control of homologous recombination: Basic mechanisms applied to novel treatments

Award Number: R01CA268641

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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