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Elucidating the role of transcriptomics in driving ethnicity and ancestry-related disparities in colorectal cancer

Award Number: R01CA284732
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Elucidating the role of transcriptomics in driving ethnicity and ancestry-related disparities in colorectal cancer - The benefits of precision oncology advances in colorectal cancer (CRC) differ across patient groups in the United States (U.S.). Prognosis remains stubbornly low in some patients. Immunotherapy has arguably been the most important advance in treatment for CRC in this past decade. This is particularly relevant for microsatellite instable tumors that harbor high mutational and neoantigen burden, where immune checkpoint inhibitors (ICIs) are highly effective and FDA-approved. However, despite dramatic activity in some CRC patients, a much larger fraction of patients do not respond. As a result, extensive efforts to understand and manipulate the tumor immune microenvironment features that influence response to ICIs and other targeted therapies are ongoing and forthcoming. Also needed are studies to identify unique molecular targets for developing new precision medicine interventions. An underexplored molecular mechanism with potential to advance the fields of immuno-oncology and targeted therapy is RNA splicing, a key step in gene expression that generates multiple ‘alternative’ mRNA transcripts, encoding functionally distinct protein isoforms that expands the functional repertoire of the genome. When dysregulated, in cancer, RNA splicing can result in pathogenic variants and immunogenic neoantigens. When neoantigens are present in high abundance, ICIs are most effective. The significance of RNA splicing in CRC is supported by a study demonstrating that splice neoantigens enhanced ICI blockade in a mouse model and studies showing that pathogenic RNA splice variants can drive every hallmark of cancer, with potential to be therapeutically targeted. Mounting evidence demonstrates that RNA splicing events are influenced by genetic ancestry and are important in CRC biology, therapeutic response and survival. Our goal is to understand the contribution of RNA splicing events to differences in treatment response and outcomes in CRC. Quantifying how genetic ancestry influences the transcriptome and outcomes will generate much-needed knowledge in CRC. Our proposal leverages existing cohorts with biospecimens and annotated data. We will address three aims: (1) characterize expression patterns of alternative mRNAs and genes encoding splicing factors by genetic ancestry and across patient characteristics that broadly represent the U.S. populations; (2) examine the role of RNA splicing in tumor-associated immune responses; and (3) determine the functional consequences of expression of prioritized RNA splice variants with respect to CRC biology in vitro and in vivo (using CRISPR/Cas9 genome edited CRC cell lines). This project will be the first of its kind to relate alternative mRNA species, neoantigens, and CRC outcomes.


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 = $660,223 )
2026	2026	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	3	3/30/2026	NON-COMPETING CONTINUATION	$660,223
														Subtotal = $660,223

Issue Date FY: 2025 ( Subtotal = $664,795 )
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	2	5/22/2025	NON-COMPETING CONTINUATION	$66,479
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	2	4/18/2025	NON-COMPETING CONTINUATION	$598,316
														Subtotal = $664,795

Issue Date FY: 2024 ( Subtotal = $719,426 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	1	4/1/2024	NEW	$719,426
														Subtotal = $719,426

Grand Total All Awards = $2,044,444

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Elucidating the role of transcriptomics in driving ethnicity and ancestry-related disparities in colorectal cancer

Award Number: R01CA284732

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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