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Exploiting oncogenic chromatin regulators in cancer initiation and progression

Award Number: K00CA264296
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Exploiting oncogenic chromatin regulators in cancer initiation and progression - PROJECT SUMMARY Genetic alterations in cancer cells can cause activation of regulatory factors that bind chromatin at target gene loci to turn on transcription programs that drive tumor initiation and progression. However, despite identification of these oncogenic regulatory factors in multiple tumor types, a gap in this rapidly evolving field is the delineation of molecular mechanisms that open opportunities to target those regulators. Thus, my long-term goal is to define interaction surfaces within chromatin-bound regulators critical for their oncogenic functions. In the F99 phase of this proposal I will focus on the transcription regulator KAP1 and its previously unprecedented role in activating oncogenic WNT signaling in colorectal cancer (CRC). Despite the well- established knowledge that WNT signaling drives CRC transformation and promotes tumor progression, a therapeutic arm that successfully inactivates WNT in CRC has yet to be employed. Potentially addressing this gap in knowledge, my studies have discovered that KAP1 is required for expression of WNT target genes in response to oncogenic WNT stimulation. Importantly, compelling preliminary data support two non-mutually exclusive mechanisms explaining how KAP1 may regulate WNT signaling. First, KAP1 could directly activate WNT by scaffolding key transcriptional machinery to WNT target gene promoters using its chromatin reader module. Second, KAP1 could interact with and regulate β-Catenin stability (the WNT transcription effector). I will test these two models and then evaluate whether perturbing the KAP1–chromatin and/or KAP1–β-Catenin interactions will block WNT-induced CRC phenotypes. In the K00 phase, I will shift focus to another biomedically relevant chromatin regulatory complex (SWI/SNF). SWI/SNF normally remodels nucleosomes on chromatin to activate target gene expression, but its dysregulation in cancer can cause aberrant activation of oncogenic programs. Likewise, in the soft-tissue malignancy Synovial Sarcoma (SS), the transforming genetic alteration is translocation of SS18, a member of SWI/SNF, to the SSX transcription factor. Because SSX, but not SSX18, normally binds modified nucleosomes, SSX abnormally redirects SS18 to a cancer-specific set of genomic sites, causing upregulation of genes that promote tumorigenesis. Despite this mechanistic understanding, the molecular and structural basis of the SS18-SSX– nucleosome interaction remains unclear, and a strategy to target SS18-SSX is currently undefined. To achieve these unmet needs, I will biophysically characterize the SS18-SSX-nucleosome interaction and then identify small-molecule inhibitors that disrupt the SS18-SSX-nucleosome interaction. Finally, I will test lead inhibitor candidates in hallmarks of cancer assays (proliferation and invasion). The training obtained under both phases will fulfill my long-term goal of running my own lab with an emphasis on molecular mechanisms of gene regulation, allowing me to have a positive impact on 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: 2026 ( Subtotal = $87,938 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Cancer Research Manpower	000	5	12/10/2025	NON-COMPETING CONTINUATION	$87,938
														Subtotal = $87,938

Issue Date FY: 2025 ( Subtotal = $97,709 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Cancer Research Manpower	003	4	3/20/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$33,520
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Cancer Research Manpower	001	4	12/26/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$97,709
2025	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	002	3	3/20/2025	EXTENSION WITH OR WITHOUT FUNDS	-$33,520
2025	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	3	12/26/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $97,709

Issue Date FY: 2024 ( Subtotal = $99,216 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	001	3	8/12/2024	EXTENSION WITH OR WITHOUT FUNDS	$6,912
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	3	12/21/2023	EXTENSION WITH OR WITHOUT FUNDS	$92,304
														Subtotal = $99,216

Grand Total All Awards = $284,863

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Exploiting oncogenic chromatin regulators in cancer initiation and progression

Award Number: K00CA264296

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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