# PI3K Pathway Mutations in Head and Neck Cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $645,333

## Abstract

Head and neck squamous cell carcinoma (HNSCC) is a morbid and lethal malignancy
where increased understanding of the genetic alterations that characterize this cancer
has yet to identify predictive biomarkers to guide therapy.PIK3CA is the most
commonly altered oncogene in both human papillomavirus (HPV)- negative (34% of
cases) and HPV-positive (56% of cases) HNSCC. In the current funding period we found
that PIK3CA mutation or amplification is a biomarker of poor prognosis in HNSCC and
that only a subset of PIK3CA- mutated HNSCC tumors are sensitive to PI3K pathway
inhibition. Further investigation suggested that HPV oncoproteins regulate the antitumor
effects of PI3K inhibitors. We hypothesize that elucidation of the biologic impact of
individual PIK3CA alterations and mechanisms of PI3K inhibitor resistance will guide
therapeutic strategies to improve clinical outcomes for HNSCC patients whose tumors
contain genetic alterations that activate PI3K signaling. To test this hypothesis we
propose three Specific Aims. Specific Aim 1 will elucidate the protein interactome and
synthetic lethal dependencies for each mutant p110α demonstrated to “drive” HNSCC
survival using: a) affinity purification- mass spectrometry (AP-MS) in HPV+ and HPV-
HNSCC models; and b) genetic interaction CRISPR screening. In Aim 2 we will
determine the impact of targeting PI3K alone and in combination with inhibition of
individual mutant p110α−interacting proteins in both immunocompetent and
immunodeficient HNSCC preclinical models. Aim 3 will examine biomarkers of PI3K
inhibitor resistance by analyzing paired biospecimens and PDXs developed from
HNSCC patients enrolled on a window-of-opportunity trial of the p110α PI3K inhibitor
BYL719. Successful completion of these studies has the potential to change clinical
practice in HNSCC by providing effective treatment strategies for patients based on the
specific PIK3CA mutational status of their tumor.

## Key facts

- **NIH application ID:** 9978809
- **Project number:** 5R01DE023685-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jennifer Rubin Grandis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $645,333
- **Award type:** 5
- **Project period:** 2014-05-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978809

## Citation

> US National Institutes of Health, RePORTER application 9978809, PI3K Pathway Mutations in Head and Neck Cancer (5R01DE023685-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978809. Licensed CC0.

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