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Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model

Award Number: R01CA262112
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model - SUMMARY: The lack of understanding how genetic variants affect molecular mechanisms that mediate TNBC aggression and impact effective anti-tumor therapies poses a substantial obstacle to advancement in cancer therapies. Current genetically engineered mouse models (GEMMs) of TNBC lack genetic complexity because mice are on a single inbred background which impairs the rigorous investigation into how individual genetic variation might impact tumor initiation, progression, or response to therapy. Because of this limitation, pre-clinical models typically fail to translate well to impact patient care. Although human studies have identified risk factors for developing TNBC with both environmental and genetics approaches, studies often fall short due to the inability to control variables or sample enough individuals. To address these limitations, we have pioneered a transformative approach with the creation of a novel murine model with robust, reliable, and reproducible phenotypic and genomic variation. We systematically crossed the C3(1)-Tantigen (C3Tag) GEMM, well established to resemble human basal-like TNBC, into the BXD family - the largest and best characterized genetic reference population. Preliminary data demonstrate that BXD-TNBC F1 isogenic hybrids have greatly differing severity of TNBC phenotypes, indicating genetic modifiers that impact disease. The advantage of the BXD-TNBC hybrids is that every genome is defined and reproducible. Using cutting edge systems genetics and molecular candidate validation, we will identify genetic modifiers of TNBC. Cross-species comparisons with publicly available human GWAS and genomic databases will identify conserved, biologically relevant, and targetable candidates to yield highly impactful and readily translatable findings. We hypothesize that the interaction of modifier and causal genes govern the heterogeneity of TNBC phenotypes and alter response to therapy. Aim 1 will identify and validate novel genetic modifiers of TNBC phenotypes through unbiased systematic quantification of TNBC severity and heritability across BXD-TNBC hybrids. Pilot studies revealed candidate genes that impact patient survival in TNBC. Aim 2 will identify and validate novel genetic modifiers of therapeutic efficacy across BXD-TNBC hybrids. Last, the genetic contribution linking obesity and TNBC is currently unknown which is a problem because obesity exacerbates poor BC outcomes and reduces therapeutic efficacy in patients. Aim 3 will identify genetic modifiers of susceptibility to obesity exacerbated TNBC. Capitalizing upon our team’s expertise, the overall objective is to interrogate this replicable genetic resource using established successful strategies to inform on the genetics of human risk and response to therapy. In sum, the lack of targeted therapies for TNBC presents a great unmet clinical need. The deliverables of this novel BXD-TNBC will define susceptibility loci, candidate genes, and molecular networks that underlie variation of multiple TNBC phenotypes. Results generated will thus be transformative with high impact, leading to the identification of genes modifying heterogeneity and networks underlying individual differences in TNBC.


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 = $408,317 )
2025	2025	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Cancer Cause and Prevention Research	000	4	1/17/2025	NON-COMPETING CONTINUATION	$367,486
2025	2025	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Cancer Cause and Prevention Research	001	4	6/12/2025	NON-COMPETING CONTINUATION	$40,831
														Subtotal = $408,317

Issue Date FY: 2024 ( Subtotal = $383,960 )
2024	2024	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Cancer Cause and Prevention Research	001	3	4/18/2024	NON-COMPETING CONTINUATION	$20,208
2024	2024	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Cancer Cause and Prevention Research	000	3	3/5/2024	NON-COMPETING CONTINUATION	$363,752
														Subtotal = $383,960

Issue Date FY: 2023 ( Subtotal = $404,735 )
2023	2023	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Cause and Prevention Research	000	2	2/7/2023	NON-COMPETING CONTINUATION	$404,735
														Subtotal = $404,735

Issue Date FY: 2022 ( Subtotal = $413,761 )
2022	2022	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Cancer Cause and Prevention Research	000	1	2/15/2022	NEW	$413,761
														Subtotal = $413,761

Grand Total All Awards = $1,610,773

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Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model

Award Number: R01CA262112

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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