# Downstream effects of HPV integration on survival/metastasis in oropharyngeal cancer

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $584,593

## Abstract

Abstract
The incidence of human papillomavirus associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC)
is rising in the US, and is now even more prevalent than cervical cancer. Due to low HPV vaccination rates
and the decades long latency period between HPV infection and cancer diagnosis, HPV+ OPSCC remains a
major health concern, with the most likely reason for death being distant metastasis. Furthermore, due to the
life-long detrimental treatment effects on quality of life for survivors, it is essential to identify a subset of
patients who would benefit from de-escalated treatment. Our long term goal is to differentiate HPV+ patients
who have a good prognosis and are most likely to benefit from de-escalated therapy and those who require the
standard, or a more aggressive regimen. Our group first characterized two main subtypes of HPV+ OPSCC,
identifying HPV integration into the host genome as the driving factor in determining tumor subtype.
Furthermore, we and others have shown that HPV integration status is associated with overall survival.
In this proposal we plan to study three downstream effects of HPV integration identified by our group and
others: an increase in the splicing of HPV oncogene E6 to E6*, a decrease in the tumor immune response, and
a change in cell differentiation status. Each of these effects plays a role in determining metastasis and
survival, however the mechanism of their effect and their relative contributions remain unclear. In aim 1, we will
disentangle the above three effects of HPV integration on overall and disease-specific survival using a
University of Michigan cohort of 300 patients, and we will compare methods for defining HPV integration
status. We will also optimize a biomarker for tumor immune infiltration based on H&E slides. In aim 2, we will
examine the oncogenic effects of the shift to expressing the shorter E6* isoform instead of full length E6, using
in vitro and in vivo models. This was observed by us and others to increase oxidative phosphorylation and
potentially tumor mutational burden. Finally, in aim 3 we will use in vitro and vivo models to examine
mechanism by which HPV integration and/or the shift to E6* expression modulate cell invasion and treatment
response. Based on our results, we will begin one or more biomarker-based pilot phase II clinical trials.

## Key facts

- **NIH application ID:** 10438782
- **Project number:** 5R01CA250214-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Nisha J D'Silva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $584,593
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438782

## Citation

> US National Institutes of Health, RePORTER application 10438782, Downstream effects of HPV integration on survival/metastasis in oropharyngeal cancer (5R01CA250214-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10438782. Licensed CC0.

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