# Targeting Signaling Vulnerabilities for Oral Cancer Prevention

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $491,893

## Abstract

Abstract
There is an urgent need to develop prevention options to halt the progression of oral premalignant lesions (OPL)
into oral squamous cell carcinoma (OSCC), a disease that results in over 250,000 deaths each year worldwide.
Our recent findings indicate that the activation of the PI3K/mTOR signaling network is the most frequently
dysregulated molecular mechanism in OSCC and OPL and that PI3K/mTOR inhibition exerts potent antitumor
activity in experimental OPL and OSCC models. We also showed that the repurposed drug metformin, which is
safely used by millions of type 2 diabetes patients, decreases mTOR signaling in OPL and OSCC and displays
potent chemopreventive activity in experimental oral premalignancy models. Based on these studies, and recent
epidemiological data showing a significant reduction in OSCC incidence in diabetic patients on metformin, we
have recently launched the NCI N01 Phase IIa Clinical Trial of metformin for oral cancer prevention trial (M4OC-
Prevent, NCT02581137) to explore the potential use of metformin for OSCC prevention. However, our
incomplete understanding of the molecular determinants of the therapeutic response to metformin in OPL or in
any other precancer lesions limits our ability to identify patients most likely to benefit from metformin. The overall
objective of our project is to elucidate the molecular mechanisms by which metformin acts on OPL and OSCC
to 1) discover novel genomic markers of response and resistance to metformin in OPL, 2) test the influence of
bioenergetic pathways involving LKB1/AMPK, and mTOR and YAP inhibition in the activity of metformin in OPL,
and 3) apply genetic screens to identify novel molecular mechanism determining response or resistance to
metformin, thereby helping prevent or overcome drug resistance. By leveraging the wealth of clinical and genetic
information and tissue and body fluid resources from our M4OC-Prevent trial with our expertise in decoding
cancer promoting pathways, the long-term goal of our team effort is to define mechanism-based biomarkers
predicting a response to metformin and suitable therapeutic options to overcome drug resistance. Ultimately, our
planned studies will provide the foundation for patient selection (enrichment) for the design and implementation
of future OSCC precision prevention trials. By focusing on a cancer of well recognized premalignant state and
readily accessible lesions for histological and molecular evaluation, our findings will also have a broad impact in
the field, as they will enable the development of metformin as an effective, safe, and low-cost preventive agent
for multiple malignancies.

## Key facts

- **NIH application ID:** 10098030
- **Project number:** 5R01DE026644-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jorge Silvio Gutkind
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $491,893
- **Award type:** 5
- **Project period:** 2017-01-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098030

## Citation

> US National Institutes of Health, RePORTER application 10098030, Targeting Signaling Vulnerabilities for Oral Cancer Prevention (5R01DE026644-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10098030. Licensed CC0.

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