Wednesday, July 2, 2025 7/2/2025

PBRM1 bromodomain missense mutations in ccRCC vascular signaling

Award Number: F30CA278386
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

Group Awards By:

View Award Description

PBRM1 bromodomain missense mutations in ccRCC vascular signaling - PROJECT SUMMARY Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma. Although outcomes are favorable with early detection and surgery, approximately 30% of patients present with metastatic disease. This highlights the need for an improved biochemical understanding of and targeted therapeutic options for ccRCC. ccRCC is a uniquely vascular cancer due to mutations in the von Hippel-Lindau (VHL) gene, which encodes the substrate recognition subunit of a ubiquitin ligase that degrades hypoxia- inducible factor-α (HIF-α) transcription factors in normoxia. VHL loss results in nuclear HIF-α accumulation and aberrant expression of downstream pro-angiogenic gene targets in a likely HIF-2α-biased manner. Thus, ccRCC tumors are uniquely susceptible to anti-angiogenic therapies, which though effective, are associated with substantial undesirable toxicities for patients. Recent clinical trials have demonstrated that mutations in Polybromo-1 (PBRM1), an epigenetic acetyl-lysine reader protein commonly mutated in ccRCC, correlate with improved outcomes for anti-angiogenic therapies. However, these studies presume that all PBRM1 mutations are loss-of-function and neglect to consider that ~15% of ccRCC-related PBRM1 mutations are missense mutations, generating full-length proteins with a spectrum of undetermined structural and functional impacts. ccRCC-associated PBRM1 missense mutations cluster in bromodomains (BDs), the functional domains of PBRM1 that bind acetyl-lysine residues in histones and other nuclear proteins and nucleic acids. Therefore, a better knowledge of the biochemical impacts of PBRM1 BD missense mutations in ccRCC is critical to promote PBRM1 as a predictive biomarker for patient response to anti-antiangiogenic therapies, so that non-responding patients can avoid unnecessary therapeutic toxicity and seek alternative treatments. This fellowship will elucidate the biochemical impacts of ccRCC-associated PBRM1 BD missense mutations on protein stability and acetylated histone binding function and determine the role of PBRM1 in the regulation of the HIF-2α and angiogenesis pathways. Aim 1 will identify which PBRM1 BD missense mutations are biochemically benign or deleterious for protein structure and function by integrating computational prediction with biophysical assay validation. Aim 2 will determine the effects of PBRM1 BD missense mutations on HIF-2α and angiogenesis pathway regulation by assessing HIF-2α transcriptional output, HIF-2α promoter accessibility, and angiogenic potential in ccRCC cellular assays. This fellowship addresses knowledge gaps in the biochemical basis of ccRCC pathogenesis with the overall goal to promote the most effective use of standard ccRCC treatment modalities. Successful completion of this fellowship will further precision medicine approaches for the treatment of ccRCC by advancing PBRM1 mutational status as a nuanced and predictive biomarker to prevent unnecessary patient drug exposures.


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 = $51,628 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Research Manpower	001	3	5/22/2025	NON-COMPETING CONTINUATION	$564
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Research Manpower	000	3	4/11/2025	NON-COMPETING CONTINUATION	$51,064
														Subtotal = $51,628

Issue Date FY: 2024 ( Subtotal = $51,064 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Research Manpower	000	2	6/3/2024	NON-COMPETING CONTINUATION	$51,064
														Subtotal = $51,064

Issue Date FY: 2023 ( Subtotal = $49,784 )
2023	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Research Manpower	001	1	4/18/2023	NEW	$0
2023	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Research Manpower	000	1	4/18/2023	NEW	$49,784
														Subtotal = $49,784

Grand Total All Awards = $152,476

Top

All Categories

About

Search

Reports

Data Submission

Award Information

PBRM1 bromodomain missense mutations in ccRCC vascular signaling

Award Number: F30CA278386

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer