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Delineating chromatin-related gene expression signatures as a function of HNSCC progression

Award Number: R01DE027809
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Delineating chromatin-related gene expression signatures as a function of HNSCC progression - Summary Oral squamous cell carcinoma (OSCC), the most common subtype of head and neck carcinoma (HNSCC), has very few targeted therapies available and poor overall survival. Novel strategies based on the high-throughput analyses offer new hope for improved risk assessment, early cancer detection, therapeutic intervention and tumor surveillance, but the impact of these strategies has been limited by an incomplete understanding of the biology of oral cancer, particularly in its early developmental stages. Like other solid malignancies, OSCCs begin as pre-neoplastic cellular proliferation that are driven by the serial acquisition of genetic and epigenetic alterations. Nearly 20% of patients with OSCC harbor multiple pre-malignant lesions showing signs of dysplasia, often visually identified as leukoplakia or erythroplakia. As some of these lesions evolve to malignant neoplasms, they represent intermediate steps in OSCC progression. This multi-step process from normal epithelium to early premalignant change to carcinoma in situ (CIS) and fully invasive carcinoma, provides a rational framework for studying molecular alterations underlying the OSCC progression. However, relatively few oncogenic mutations critical to the development of OSCC are currently recognized, impeding discovery of novel targeted therapeutics. Moreover, mutations alone are insufficient to explain the broad spectrum of gene expression changes that characterize OSCC. Whole-genome distribution of enhancers, the functional elements of the chromatin, is associated with the development of multiple solid malignancies, and mediates widespread genomic changes including expression of known cancer driver genes. Although it is becoming apparent that enhancers are the critical regulators of their target genes, and enhancer genomic elements are rapidly emerging as potent targets for anti-cancer therapeutics, the association between chromatin modifications and gene expression patterns in OSCC is not yet defined, and no comprehensive molecular information is available in oral pre-neoplastic lesions. This project will use novel bioinformatics and experimental approaches to test the central hypothesis that transcriptional changes, which arise during OSCC carcinogenesis, are enabled by dynamic chromatin alterations. Our integrated analysis will couple the gene expression and methylation landscape with a corresponding evaluation of the cancer- specific enhancer phenotype throughout the continuum of OSCC progression. Characterizing the timing and manner by which gene expression alterations coincide with markers of chromatin organization in sequentially progressive lesions within the oral cavity (e.g. mild dysplasia, moderate dysplasia, severe dysplasia/CIS, and invasive OSCC) will yield the first comprehensive epigenetic map of HNSCC evolution, and will define the key epigenetically regulated genes that drive OSCC carcinogenesis. Furthermore, evaluating their biological and clinical relevance may open up a fertile avenue for developing novel intervention strategies targeting these genes at various developmental stages of HNSCC.


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: 2023 ( Subtotal = $325,949 )
2023	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	001	6	6/29/2023	NON-COMPETING CONTINUATION	-$95,519
2023	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	000	6	5/2/2023	NON-COMPETING CONTINUATION	$421,468
														Subtotal = $325,949

Issue Date FY: 2022 ( Subtotal = $407,176 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	002	5	5/9/2022	NON-COMPETING CONTINUATION	$407,176
2022	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	001	4	3/21/2022	NON-COMPETING CONTINUATION	$0
2022	2020	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	000	1	3/17/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $407,176

Issue Date FY: 2021 ( Subtotal = $426,551 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	002	4	4/8/2021	NON-COMPETING CONTINUATION	$550,112
2021	2020	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	000	2	2/5/2021	NON-COMPETING CONTINUATION	-$599,252
2021	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	001	3	2/8/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$475,691
2021	2020	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	005	1	7/16/2021	SUPPLEMENT FOR EXPANSION	-$68,228
2021	2020	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	004	2	7/16/2021	NON-COMPETING CONTINUATION	-$171,704
2021	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	006	3	7/16/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$360,581
2021	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	003	1	7/16/2021	NEW	-$120,649
														Subtotal = $426,551

Issue Date FY: 2020 ( Subtotal = $839,184 )
2020	2020	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	001	2	3/20/2020	NON-COMPETING CONTINUATION	$770,956
2020	2020	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	000	1	11/29/2019	SUPPLEMENT FOR EXPANSION	$68,228
														Subtotal = $839,184

Issue Date FY: 2019 ( Subtotal = $587,622 )
2019	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Oral Diseases and Disorders Research	000	1	4/30/2019	NEW	$587,622
														Subtotal = $587,622

Grand Total All Awards = $2,586,482

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Delineating chromatin-related gene expression signatures as a function of HNSCC progression

Award Number: R01DE027809

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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