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Pan-Cancer characterization of 3’UTR somatic mutations controlling tumor immune evasion

Award Number: R01CA258776
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Pan-Cancer characterization of 3’UTR somatic mutations controlling tumor immune evasion - SUMMARY All stages of neoplastic disease, from its development to metastasis, are intertwined with cancer immune evasion. The epigenetic mechanisms involved in the regulation of the tumor immune landscape are intensely investigated as biomarkers or therapeutic targets. 3' untranslated regions (3'UTRs) dictate the post- transcriptional mRNA fate and are often targeted by regulatory molecules such as microRNAs (miRNAs) and RNA binding proteins (RBPs). Tumor cells have been shown to evade this tight regulation by mutating or truncating these regions. The first such identified events have shed light on somatic regulatory mechanisms that could potentially affect tumor immune evasion, response to immunotherapy, and patient management. However, the transcriptome-wide detection, validation, and functional characterization of 3'UTR somatic events and their effects on the tumor immune landscape are still pressing -yet unmet- needs. In this project we will deploy an in silico/experimental framework that combines massively parallel variant validation, spatial transcriptomics, and bioinformatic detection/functionalization technologies to characterize Pan-Cancer and transcriptome-wide 3'UTR somatic mutation/truncation events, as well as to assess their potential as immunoediting mechanisms, markers for patient stratification, and novel therapeutic targets. Aim 1: By efficiently integrating raw multi-omic datasets, we will identify somatic 3'UTR mutations and truncations in more than 10,000 cancer patients across 33 cancer types. We will prioritize all 3'UTR variants affecting gene expression in cis, delineating the 3'UTR-mediated regulatory landscape across cancer types. Aim 2: We will identify mutations and disrupted circuitry affecting cancer immunophenotypes and the tumor microenvironment. We will utilize extensive post-transcriptional data/experimental resources to uncover the regulators (miRNAs, RBPs) and mechanisms involved in such immunoediting events. Aim 3a: We will validate up to 20,000 somatic 3'UTR events using a massively parallel sequencing technology. Prioritized interactions will be investigated in vitro as well as using a biomimetic 3D device to characterize their effects on gene regulation and T-Cell killing, while patient samples will be investigated using spatial transcriptomics. Aim 3b) We will assess the translational potential of the leading 3'UTR events and genes as predictors of immunotherapy response using Deep Learning models, against an extensive cohort of >300 cancer patients treated with immune checkpoint inhibition. We are uniquely suited to perform this in-depth characterization, since our research team comprises leading post transcriptional regulation and immune-oncology researchers, while the relevant resources (in silico, experimental, samples) are already in place. We will perform the first Pan-Cancer and transcriptome-wide investigation of tumor immune evasion by 3'UTR somatic mutations and truncations. We will use an innovative in silico-experimental framework to identify 3'UTR events, miRNAs, and RBPs that can be used as markers for efficient patient stratification as well as novel immunotherapeutic targets.


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 = $507,623 )
2026	2026	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	5	1/16/2026	NON-COMPETING CONTINUATION	$507,623
														Subtotal = $507,623

Issue Date FY: 2025 ( Subtotal = $588,394 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	4	1/22/2025	NON-COMPETING CONTINUATION	$529,555
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	4	6/2/2025	NON-COMPETING CONTINUATION	$58,839
														Subtotal = $588,394

Issue Date FY: 2024 ( Subtotal = $540,818 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	3	1/23/2024	NON-COMPETING CONTINUATION	$512,353
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$28,465
														Subtotal = $540,818

Issue Date FY: 2023 ( Subtotal = $610,423 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	2	1/27/2023	NON-COMPETING CONTINUATION	$610,423
														Subtotal = $610,423

Issue Date FY: 2022 ( Subtotal = $618,468 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	1	1/26/2022	NEW	$618,468
														Subtotal = $618,468

Grand Total All Awards = $2,865,726

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Pan-Cancer characterization of 3’UTR somatic mutations controlling tumor immune evasion

Award Number: R01CA258776

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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