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Immune and transcriptomic biomarkers of progressive oral premalignant lesions

Award Number: U01DE033351
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Immune and transcriptomic biomarkers of progressive oral premalignant lesions - PROJECT SUMMARY Oral squamous cell carcinoma (OSCC) is the 6th leading cause of cancer-related mortality worldwide. OSCC is curable with favorable survival outcomes if detected early. The majority of OSCCs are preceded by oral potentially malignant disorders (OPMDs) with oral leukoplakia or white lesions being the most common type. However, not all oral leukoplakia progresses to OSCC. Accurate identification of OPMDs that are likely to progress to OSCC offers the best strategy for OSCC prevention and management and can lead to decreasing patients’ morbidity and mortality through earlier detection. Although proven inadequate, microscopic examination and histological grading remain the gold standard for predication of malignant transformation. For instance, some low-grade OPMDs will progress to OSCC but not all high-grade OPMDs progress to OSCC. There is an urgent and unmet demand for highly efficacious biomarkers to identify progressive leukoplakias with a high risk of OSCC conversion. Addressing this knowledge gap can lead to early detection of HPV-negative OSCC and improve patient survival. Examining OPMDs with and without malignant transformation, we have found specific transcriptomic signatures which are associated with progressive OPMDs. Using spatial transcriptomics and multiplex immune fluorescence (mIF), we observed that malignantly transformed OPMDs have significantly increased immunosuppressive tumor-associated macrophages (enriched in ARG1) and low levels of CD8+ T- cells. Our central hypothesis is that the levels and trajectories of such signatures in tissues are predictive of the malignant conversion of OPMDs to OSCC. The primary objective of this multi-disciplinary U01 collaborative study is to identify and validate transcriptomic and immune signatures that can discriminate OPMDs predicted to malignantly progress and develop, validate, and refine a risk stratification model based on identified biomarkers and clinical variables. In Aims 1 and 2, we will leverage a well-characterized, racially diverse population of over 500 individuals with histologically confirmed OPMDs. We will validate our list of transcriptomic and immune-related biomarkers and perform RNA sequencing and spatial transcriptomics to identify potential additional transcripts associated with the malignant progression of OPMDs. In Aim 3, we will develop a combination risk score formula based on selected transcriptomics and immune biomarkers and clinicodemographic variables to predict OMPD malignant progression based on our internal cohort. We will validate the combination risk score formula in an independent cohort of 300 patients. The risk score formula can be used by clinicians for risk assessment and clinical decision making. The contribution from this project is expected to be significant as it can lead to introduction of a personalized risk stratification approach for management of OPMDs. Detecting preneoplastic lesions with high malignant transformation risk will substantially increase patient survival while maximizing OSCC screening benefits.


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 = $814,133 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	4	8/21/2026	NON-COMPETING CONTINUATION	$814,133
2026	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	2	4/6/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $814,133

Issue Date FY: 2025 ( Subtotal = $816,981 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	003	3	8/7/2025	NON-COMPETING CONTINUATION	$816,981
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	2	10/29/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	002	2	3/10/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Oral Diseases and Disorders Research	001	1	2/12/2025	NEW	$0
														Subtotal = $816,981

Issue Date FY: 2024 ( Subtotal = $721,826 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	002	2	7/31/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$721,826
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Oral Diseases and Disorders Research	001	1	7/31/2024	NEW	$0
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Oral Diseases and Disorders Research	000	1	1/9/2024	NEW	$0
														Subtotal = $721,826

Issue Date FY: 2023 ( Subtotal = $743,064 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Oral Diseases and Disorders Research	000	1	8/29/2023	NEW	$743,064
														Subtotal = $743,064

Grand Total All Awards = $3,096,004

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Immune and transcriptomic biomarkers of progressive oral premalignant lesions

Award Number: U01DE033351

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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