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DELINEATING THE EVOLUTION AND ECOLOGY OF CHEMORESISTANCE IN BREAST CANCER WITH SINGLE CELL GENOMICS

Award Number: R01CA236864
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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DELINEATING THE EVOLUTION AND ECOLOGY OF CHEMORESISTANCE IN BREAST CANCER WITH SINGLE CELL GENOMICS - PROJECT SUMMARY Triple-negative breast cancer (TNBC) is an aggressive subtype in which patients display extensive intratumor genomic heterogeneity and frequently (50%) develop resistance to neoadjuvant chemotherapy (NAC) which leads to metastatic disease and death. Due to the absence of hormonal receptors and targeted therapies, TNBC patients with refractory disease are often left with limited treatment options. Currently, our understanding of the genomic evolution of tumor cells and the role of the tumor microenvironment in chemoresistant disease at primary and metastatic organ sites represents a major gap in knowledge that this proposal aims to address. Our group has developed cutting-edge single cell DNA and RNA sequencing technologies that can overcome previous technical barriers and limitations with `bulk' genomic methods for studying the genomic and phenotypic evolution of tumor cells in response to chemotherapy. Our preliminary data in a small number of TNBC patients suggests that genomic evolution of chemoresistance occurs through the adaptive selection of pre-existing mutations and copy number alterations, which is followed by transcriptional reprogramming, to achieve a chemoresistant phenotype (Kim et al. 2018, Cell). We further hypothesize that transcriptional reprogramming of cell types in the tumor microenvironment occurs in chemoresistant disease and that resistance programs are clonally inherited at distant metastatic organ sites. To comprehensively investigate these questions in matched longitudinal samples from TNBC patients in a large neoadjuvant chemotherapy trial (ARTEMIS), we propose three synergistic aims: Aim 1 will determine if copy number aberrations (CNAs) and subclonal mutations associated with chemoresistance are pre-existing and adaptively selected in response to therapy. Aim 2 will investigate if tumor cells and cell types in the microenvironment undergo transcriptional reprogramming in refractory disease. Aim 3 will determine if subpopulations of resistant cells in the primary tumor seed the metastatic lesions and confer resistance programs at distant organ sites. Completion of these aims will define the genomic and evolutionary basis of chemoresistance in TNBC patients and will provide new diagnostic biomarkers and therapeutic targets for overcoming chemoresistant disease, which is a critical unmet clinical need. Our long-term goal is to translate single cell sequencing technologies into the clinic, where they are poised to have a major impact on the diagnosis and treatment of breast cancer patients. The proposed aims are directly aligned with the mission of NIH to reduce morbidity and improve the quality of life for breast cancer patients.


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: 2024 ( Subtotal = $352,047 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	001	5	4/15/2024	NON-COMPETING CONTINUATION	$18,529
2024	2024	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	5	11/20/2023	NON-COMPETING CONTINUATION	$333,518
														Subtotal = $352,047

Issue Date FY: 2023 ( Subtotal = $363,164 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	4	11/16/2022	NON-COMPETING CONTINUATION	$333,518
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	001	4	3/15/2023	NON-COMPETING CONTINUATION	$29,646
														Subtotal = $363,164

Issue Date FY: 2022 ( Subtotal = $363,164 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	3	11/19/2021	NON-COMPETING CONTINUATION	$333,517
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	001	3	5/20/2022	NON-COMPETING CONTINUATION	$29,647
														Subtotal = $363,164

Issue Date FY: 2021 ( Subtotal = $620,575 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	001	2	2/8/2021	NON-COMPETING CONTINUATION	$31,030
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	2	11/30/2020	NON-COMPETING CONTINUATION	$589,545
														Subtotal = $620,575

Issue Date FY: 2020 ( Subtotal = $620,575 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	1	11/20/2019	NEW	$370,575
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	001	1	9/15/2020	NEW	$250,000
														Subtotal = $620,575

Grand Total All Awards = $2,319,525

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DELINEATING THE EVOLUTION AND ECOLOGY OF CHEMORESISTANCE IN BREAST CANCER WITH SINGLE CELL GENOMICS

Award Number: R01CA236864

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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