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Dissecting Transcription Factor-Mediated Chromatin remodeling Complex Activities in Human Cancer

Award Number: K99CA315559
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Dissecting Transcription Factor-Mediated Chromatin remodeling Complex Activities in Human Cancer - PROJECT SUMMARY Cancer cells frequently co-opt master regulatory transcription factors (TFs) to drive aberrant gene expression programs. The mammalian SWI/SNF (mSWI/SNF or BAF) family of ATP-dependent chromatin remodeling complexes are critical cofactors for such oncogenic TFs, facilitating accessibility at cis-regulatory elements genome-wide. While broad BAF ATPase inhibition exhibits potent antitumoral activity, toxicities associated with systemic inhibition remain challenges to success of these approaches in the clinic. The central hypothesis of this proposal is that disruption of selective BAF-TF interfaces can impair cancer-specific transcriptional programs. We aim to define the structural and functional basis of BAF recruitment by TFs in cancer cells and leverage this knowledge to develop targeted therapeutic strategies. Our recent discovery of a TF binding domain, termed SWIFT, within BAF complexes provides us with a unique opportunity to accomplish these goals (Jain et. al. 2025). In this project, we will: (1) define the biochemical and structural basis of TF interactions with BAF complexes through the SWIFT domain; (2) elucidate the consequences of disrupting SWIFT-mediated BAF-TF interactions on genomic targeting of BAF complexes, oncogenic chromatin accessibility and transcription, and cell fitness; (3) evaluate the impact of genetic and chemical targeting of the SWIFT domain on cancer cell fitness; and (4) identify and develop small molecule inhibitors of SMARCD subunit paralog-specific SWIFT-TF interactions to attenuate oncogenic activities of selective TF families. By integrating biochemistry, structural biology, functional genomics and chemical biology-based approaches, this study will inform new mechanistic foundations with translational relevance in addressing the large collection of TF-addicted human cancers.


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: 2026 ( Subtotal = $144,035 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	1	8/28/2026	NEW	$144,035
														Subtotal = $144,035

Grand Total All Awards = $144,035

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Dissecting Transcription Factor-Mediated Chromatin remodeling Complex Activities in Human Cancer

Award Number: K99CA315559

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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