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Assessment of strategies for targeting transcriptional co-activators in colorectal cancer

Award Number: R37CA293214
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Assessment of strategies for targeting transcriptional co-activators in colorectal cancer - Project Summary: PGC-1 family proteins (PGC-1α, PGC-1β, and PPRC1) are transcriptional coactivators that act as central hubs to coordinate diverse cellular inputs to promote the transcription of genes that regulate metabolism to maintain homeostasis. Transcriptional coactivator Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 β (PGC-1β) is over-expressed in colorectal cancers (CRC) with K-Ras mutations and promotes the survival of tumor cells. PGC-1 family proteins lack intrinsic enzymatic activity and function by facilitating interactions between transcription factors, epigenetic modifiers, and transcription initiation machinery. To identify the protein-protein interactions required by PGC-1β to promote gene expression we immunoprecipitated PGC- 1β and identified binding partners by mass spectrometry. Our data reveal that Estrogen-Related Receptor α (ERRα) and Host Cell Factor 2 (HCF2) are PGC-1β binding proteins that we propose are required for PGC-1β to regulate the transcription of genes that promote CRC survival. Our long-term goal is to inhibit CRC growth by blocking PGC-1β signaling and we propose that can be achieved by preventing PGC-1β from signaling through either ERRα or HCF2. In Aim 1, we will determine the mechanism by which phosphatase PGAM5 modifies PGC-1β to increase ERRα transcription. In Aim 2, we will identify PGC-1β-HCF2 regulated genes and determine the requirements for HCF2 signaling. In Aim 3, we will test the loss of the PGC-1β, the loss of the PGC-1β-ERRα interaction, the loss of the PGC-1β-HCF2 interaction, and the loss of both interactions in vivo using orthotopic submucosal injections in immunodeficient mice receiving Crispr-Cas9-modified patient-derived tumor organoids establish from liver metastases.


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 = $446,399 )
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Cancer Cause and Prevention Research	000	2	7/31/2025	NON-COMPETING CONTINUATION	$446,399
														Subtotal = $446,399

Issue Date FY: 2024 ( Subtotal = $439,367 )
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Cause and Prevention Research	000	1	8/7/2024	NEW	$439,367
														Subtotal = $439,367

Grand Total All Awards = $885,766

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Assessment of strategies for targeting transcriptional co-activators in colorectal cancer

Award Number: R37CA293214

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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