# Targeting Signaling Vulnerabilities for Oral Cancer Prevention

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $475,111

## Abstract

Abstract
There is an urgent need to develop prevention strategies to halt progression of oral premalignant lesions (OPL)
into head and neck squamous cell carcinoma (HNSCC), a disease that results in over 300,000 deaths each year
worldwide. Our team discovered that activation of the PI3K/mTOR signaling network is the most frequently
dysregulated cancer-driving signaling mechanism in HNSCC and OPLs and that, in turn, PI3K/mTOR inhibition
exerts potent antitumor activity in experimental OPL and HNSCC models. These findings provided the foundation
for our Phase II clinical trial (NCT01195922) exploring the antitumor activity mTOR blockade in HNSCC patients.
More recently, we showed that repurposing metformin, a drug safely used by millions of type 2 diabetes (T2DM)
patients, decreases mTOR signaling and displays potent chemopreventive activity in experimental OPL models.
Based on these findings, and epidemiological data showing a significantly lower HNSCC incidence in T2DM
patients on metformin, we conducted a Phase IIa trial in individuals with OPL to explore the potential of metformin
to prevent oral cancer (M4OC-Prevent trial; NCT02581137). This represented the first study evaluating the
chemopreventive potential of metformin in OPL. The histologic response rate was 60%, and we found a
significant correlation between histological response and mTOR inhibition in OPL. These results provided the
foundation for launching a multi-institutional NCI-funded Cancer Prevention Clinical Trial (M4OC-Prevent 2.0),
a Phase IIb randomized, double-blind, placebo-controlled trial in current and former smokers with OPL to explore
the potential of metformin for oral cancer prevention. However, we still have an incomplete understanding of the
molecular determinants of the therapeutic response to metformin in OPL or in any other precancerous lesions.
The overall objective of this project is to elucidate the molecular mechanisms by which metformin acts on OPL
and HNSCC to (a) identify biomarkers for predicting and monitoring clinical response, (b) provide a rationale for
mechanism-based multimodal precision chemoprevention strategies, and (c) prevent and overcome drug
resistance. Leveraging the wealth of data from clinical, genetic, and tissue specimens from our M4OC-Prevent
trial with our team’s expertise in decoding cancer promoting pathways, the long-term goal of our project is to
define (1) mechanistic biomarkers predicting a response to metformin and (2) suitable multimodal therapeutic
options to overcome drug resistance. Our planned studies will uncover new mechanistic and genetic
determinants of metformin sensitivity to inform patient selection in future precision prevention trials, unveil novel
mechanisms by which metformin induces histological response in OPL by the concomitant inhibition of mTOR
and YAP1 signaling, and provide insights into novel a precision immune prevention strategy for metformin-
resistant OPL lesions. By focusing on a cancer with a well-r...

## Key facts

- **NIH application ID:** 10540202
- **Project number:** 2R01DE026644-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jorge Silvio Gutkind
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $475,111
- **Award type:** 2
- **Project period:** 2017-01-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10540202

## Citation

> US National Institutes of Health, RePORTER application 10540202, Targeting Signaling Vulnerabilities for Oral Cancer Prevention (2R01DE026644-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10540202. Licensed CC0.

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