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Determining the functional epigenomic consequences of HPV viral oncogene expression heterogeneity in oropharyngeal squamous cell carcinoma

Award Number: F30CA313986
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2026
PERIOD OF PERFORMANCE END DATE: 09/29/2027

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Determining the functional epigenomic consequences of HPV viral oncogene expression heterogeneity in oropharyngeal squamous cell carcinoma - PROJECT SUMMARY Head and neck squamous cell cancer (HNSCC) is the seventh leading cause of cancer-related mortality worldwide, primarily driven by human papilloma virus (HPV+) or tobacco and alcohol exposure (HPV-). HNSCC incidence continues to rise dramatically, driven substantially by an increase in HPV+ HNSCC, which primarily arises from the oropharynx (OPSCC). Although HPV+ OPSCC generally demonstrates a better prognosis compared to HPV- OPSCC, approximately 30% of HPV+ OPSCC patients experience poor outcomes without clear predictive markers of treatment response. Risk stratification to de-escalate treatment for HPV+ OPSCC patients remains a major challenge as current biomarkers do not accurately predict clinical outcomes. Thus, identifying strategies to improve HPV+ OPSCC outcomes and understanding the mechanisms governing treatment response rates are timely and impactful questions that must be answered. We recently discovered that intra-tumoral diversity of HPV viral gene expression corresponds to distinct cellular states. We identified subpopulations of malignant cells in which HPV is repressed (which we termed HPVoff) leading to reduction or absence of viral gene expression (e.g. E5, E6, E7) compared to malignant cell subsets in which HPV expression is maintained (HPVon). Strikingly, HPVoff cells are enriched for a senescence-like metaprogram (EpiSen), with functional assays demonstrating reduced proliferation and resistance to radiation/chemotherapy. However, the regulation of viral gene expression in the HPVoff state and the mechanisms by which repression of HPV gene expression contributes to cellular phenotypes remain unclear. The goal of this proposal is to understand the epigenomic mechanisms driving intra-tumoral heterogeneity and how repression of viral gene expression in the HPVoff state contributes to cellular phenotypes, which may reveal translatable targets or biomarkers to direct clinical management decisions. In Aim 1, we will use single-cell RNA-seq and CRISPRi knockdown approaches in patient-derived organoid (PDO) models to identify genes contributing to cytotoxic therapy resistance in HPVoff cells and investigate the utility of these genes as biomarkers for HPV+ OPSCC clinical outcomes. In Aim 2, we will use state-of-the-art single-cell technologies and PDOs to unravel the epigenetic mechanisms governing viral gene suppression and observed phenotypes in HPVoff cells. The proposed research will provide mechanistic insight into the functional effects of HPV viral gene expression heterogeneity and mechanisms governing HPV regulation in HPV+ OPSCC tumors, which may serve as translatable targets or biomarkers to direct clinical management decisions. During this fellowship, I will assemble a mentorship committee composed of physician- scientists and experts in cancer and epigenetics research to provide both scientific and clinical mentorship. My proposed training will allow me to accomplish my goal of developing as an independent, academic physician- scientist investigating functional epigenomic mechanisms of cancer progression.


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 = $37,249 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	001	1	4/16/2026	NEW	$576
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	000	1	3/30/2026	NEW	$36,673
														Subtotal = $37,249

Grand Total All Awards = $37,249

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Determining the functional epigenomic consequences of HPV viral oncogene expression heterogeneity in oropharyngeal squamous cell carcinoma

Award Number: F30CA313986

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2026

PERIOD OF PERFORMANCE END DATE: 09/29/2027

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