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Notch-driven Epigenetic Program of MYC and CCND1 in Triple-Negative Breast Cancer

Award Number: R01CA230800
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: 11/30/2025

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Notch-driven Epigenetic Program of MYC and CCND1 in Triple-Negative Breast Cancer - Project Summary Triple-negative breast cancer (TNBC) accounts for ~10% of all the breast cancer cases, but its survival rate is lower due to the lack of effective targeted treatments. This underscores the importance of finding new treatments for therapy-resistant TNBC, which is further complicated by the disease heterogeneity. Unfortunately, success of targeted therapies in TNBC has been limited, partly due to the lack of a detailed and mechanistic understanding of the drivers of each disease subgroup. An important contributor to the TNBC pathobiology is Notch signaling. Hyperactive Notch signaling promotes tumor growth, increases chemotherapy resistance, decreases survival, and increases the chance of metastases. Although the biomarkers of the Notch-active TNBC subgroup and drugs to target Notch signaling have been recently developed, treating patients with Notch inhibitory agents has been ineffective to date, partly due to the limited understanding of how the Notch signaling controls these fundamental processes. An important direct consequence of Notch signaling is to activate key TNBC genes, including MYC, CCND1 and SOX9. MYC is one of the most important proto-oncogenes promoting tumor growth and survival. CCND1 controls cell division among other cellular processes. SOX9 increases metastatic potential. Despite their importance, existing drugs fail to directly target these proteins. We propose to leverage the regulatory relationships between Notch and its target genes to selectively and efficiently target them. In order to achieve this goal, we first need to understand the mechanisms by which Notch regulates MYC, CCND1, and SOX9 in TNBC. We propose to use cutting-edge functional genomics and chromatin conformation assays to elucidate their Notch-directed regulatory mechanisms at population and single-cell resolutions. To develop more potent therapeutic options, we plan to use the latest single-cell resolution technologies to discover how drug-resistant cells circumvent the effect of Notch inhibitory drugs and maintain the expression of these critical Notch targets. We plan to use this knowledge in the future to tailor therapeutic strategies for individual TNBC patients with activated Notch signaling, and in the process, hope to improve the survival of patients with this aggressive and difficult to treat form of breast cancer. !


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 = $231,308 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	6	11/25/2024	NON-COMPETING CONTINUATION	$208,178
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	6	5/29/2025	NON-COMPETING CONTINUATION	$23,130
														Subtotal = $231,308

Issue Date FY: 2024 ( Subtotal = $394,246 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	5	11/30/2023	NON-COMPETING CONTINUATION	$373,497
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	5	4/16/2024	NON-COMPETING CONTINUATION	$20,749
														Subtotal = $394,246

Issue Date FY: 2023 ( Subtotal = $407,447 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	4	3/15/2023	NON-COMPETING CONTINUATION	$33,260
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	4	12/14/2022	NON-COMPETING CONTINUATION	$374,187
														Subtotal = $407,447

Issue Date FY: 2022 ( Subtotal = $420,652 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	3	5/31/2022	NON-COMPETING CONTINUATION	$42,065
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	3	11/4/2021	NON-COMPETING CONTINUATION	$378,587
														Subtotal = $420,652

Issue Date FY: 2021 ( Subtotal = $193,484 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	2	7/13/2021	NON-COMPETING CONTINUATION	$21,240
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	2	11/13/2020	NON-COMPETING CONTINUATION	$172,244
														Subtotal = $193,484

Issue Date FY: 2020 ( Subtotal = $427,580 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	1	1/27/2020	NEW	$10,302
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	1	11/27/2019	NEW	$417,278
														Subtotal = $427,580

Grand Total All Awards = $2,074,717

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Notch-driven Epigenetic Program of MYC and CCND1 in Triple-Negative Breast Cancer

Award Number: R01CA230800

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: 11/30/2025

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