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Hijacking cancer driver to activate cell death by chemically induced proximity

Award Number: F30CA268848
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/21/2022
PERIOD OF PERFORMANCE END DATE: 06/20/2025

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Hijacking cancer driver to activate cell death by chemically induced proximity - Abstract Personalized targeted cancer therapy, while initially effective, leads to resistance and disease progression in >50% of patients in as rapidly as few months after initiating therapy. These therapies directly inhibit the catalytic and/or ligand-induced functions of the cancer driver, leading to resistance via mutational escape or epigenetic/transcriptional bypass. To address mutational escape, recent therapeutic approaches leverage Chemically induced Proximity (CiP): bifunctional molecules that recruit two proteins into proximity for an emergent therapeutic effect. However, current CiP-based therapies are limited to degradation, which suffers from similar feedback mechanisms of resistance as direct inhibition of the cancer driver. Then, we recognized that 45% of all cancer genes are direct transcriptional regulators. Therefore, this proposal outlines a novel CiP- enabled therapeutic paradigm to hijack cancer drivers to amplify a therapeutic transcriptional program to directly kill cancer cells. Specifically, the goal of this proposal is to hijack the estrogen receptor in breast cancer to drive overexpression of pro-apoptotic factors to induce cancer cell death. First, I will systematically define the most potent pro- apoptotic factors for transcriptional upregulation induced cell death across multiple estrogen receptor positive breast cancer cell lines. Second, I will identify and validate transcription factors that regulate these pro- apoptotic factors by integrating bioinformatic analysis with a high throughput transactivator inducible recruitment screen. Finally, I will demonstrate that estrogen receptor in breast cancer can be hijacked for targeted transcriptional upregulation by recruiting it to an endogenously tagged transcription factor regulator of potent pro-apoptotic factors and to a targeted dCas9. Together, I will identify and demonstrate that estrogen receptor can be inducibly recruited by CiP to a transcription factor regulator of pro-apoptotic factors to induce breast cancer cell death. The successful completion of the aims described will establish not only a novel therapeutic approach for estrogen receptor positive breast cancer but also a generalizable therapeutic paradigm across multiple cancer types with transactivating cancer drivers. Furthermore, I will identify robust candidates for subsequent therapeutic heterobifunctional molecule development. The proposal presented also reflects my training goals of becoming an interdisciplinary physician-scientist bridging chemical biology tools and epigenetic gene regulation to address critical problems and needs in cancer biology and therapy.


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 = $44,448 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	3	8/20/2024	NON-COMPETING CONTINUATION	$3,000
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	3	5/24/2024	NON-COMPETING CONTINUATION	$41,448
														Subtotal = $44,448

Issue Date FY: 2023 ( Subtotal = $40,168 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	2	5/17/2023	NON-COMPETING CONTINUATION	$40,168
														Subtotal = $40,168

Issue Date FY: 2022 ( Subtotal = $39,226 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	1	12/22/2021	NEW	$0
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	002	1	8/10/2022	NEW	$716
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	1	12/22/2021	NEW	$38,510
														Subtotal = $39,226

Grand Total All Awards = $123,842

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Hijacking cancer driver to activate cell death by chemically induced proximity

Award Number: F30CA268848

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/21/2022

PERIOD OF PERFORMANCE END DATE: 06/20/2025

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