Monday, June 30, 2025 6/30/2025

Delineating developmental programs driving tumorigenesis in triple-negative breast cancer

Award Number: R01CA255450
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Delineating developmental programs driving tumorigenesis in triple-negative breast cancer - PROJECT SUMMARY Triple-negative breast cancer (TNBC) is the deadliest and 2nd most common subtype of breast cancer in the United States. Although promising new drugs based on PARP inhibition and immunotherapy can extend survival in selected patients, 1 in 3 patients die from TNBC. Increasing evidence suggests that human breast tumors harbor immature cancer cells which are a distinct subset of tumorigenic cancer cells, are less-differentiated, capable of replenishing cancer cell populations indefinitely, and strongly implicated in drug resistance. Unfortunately, existing marker genes for studying these cells are not specific, precluding rational drug development. We hypothesize that precise identification of immature cancer cells could present new therapeutic opportunities to revolutionize TNBC treatment. We recently showed that the number of expressed genes per cell is a powerful surrogate of cellular differentiation status independently of known marker genes. We leveraged this finding to develop CytoTRACE, a new framework for predicting cellular differentiation status from single-cell RNA sequencing (scRNA-seq) data. Our published data show that immature cancer cells predicted by CytoTRACE preferentially express genes essential for tumorigenicity in TNBC. In pilot data, we identified 10 putative cancer cell populations, including at least 3 immature ones, from scRNA-seq data of 19 primary breast tumors. Here, we propose to study over 800 TNBC patients to determine whether immature cancer cells represent at least 3 distinct populations (Aim 1); differ by key clinical covariates (Aim 2); and are clonogenic and produce specific progeny populations predicted in silico (Aim 3). To accomplish these aims, we will leverage new analytical methods, including a deconvolution approach for integrating scRNA-seq with bulk tumor transcriptomic data in order to characterize cellular heterogeneity at scale. Successful completion of the proposed project will validate and refine our pilot data toward advancing our understanding of cancer cell populations, especially immature cells, in TNBC. As such, we expect this study to facilitate new opportunities for the development of targeted drugs to improve TNBC outcomes.


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 = $515,747 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	001	5	6/2/2025	NON-COMPETING CONTINUATION	$51,575
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	5	1/9/2025	NON-COMPETING CONTINUATION	$464,172
														Subtotal = $515,747

Issue Date FY: 2024 ( Subtotal = $489,960 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$25,788
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	4	2/15/2024	NON-COMPETING CONTINUATION	$464,172
														Subtotal = $489,960

Issue Date FY: 2023 ( Subtotal = $505,432 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	3	2/1/2023	NON-COMPETING CONTINUATION	$505,432
														Subtotal = $505,432

Issue Date FY: 2022 ( Subtotal = $515,747 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	001	2	5/16/2022	NON-COMPETING CONTINUATION	$41,260
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	2	1/31/2022	NON-COMPETING CONTINUATION	$464,172
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	002	2	8/23/2022	NON-COMPETING CONTINUATION	$10,315
														Subtotal = $515,747

Issue Date FY: 2021 ( Subtotal = $516,386 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	001	1	2/1/2021	NEW	-$324
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	1	1/28/2021	NEW	$516,710
														Subtotal = $516,386

Grand Total All Awards = $2,543,272

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Delineating developmental programs driving tumorigenesis in triple-negative breast cancer

Award Number: R01CA255450

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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