# Exploiting the HER3-PI3K/mTOR-Immune Axis to Design Precision Immune Oncology Therapy for Head & Neck Cancer

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $72,230

## Abstract

Abstract
Checkpoint blockade inhibitors (CBI) have revolutionized the care of head and neck cancer (HNC) patients, but
overall response rates to CBI remain limited at ~15-20%. This highlights the urgent need to design novel immune
oncology (IO) therapies that improve outcome by both overcoming dominant pro-survival pathways in the tumor
and reinstating effective, anticancer immunosurveillance. I hypothesize that rationally designed IO therapy, which
simultaneously targets key HNC oncogenic signaling pathways and initiates effective anticancer
immunosurveillance, is required in order to achieve durable responses. Recent breakthrough discoveries reveal
PI3K/mTOR signaling as the most frequently dysregulated network in HNCs, persistently activated in >80% of
all HNCs, and that mTOR inhibition acts as a potent antitumor agent in both experimental models of HNC and
in a recent Phase 2 clinical trial (NCT01195922). A kinome-wide RNAi screen to identify drivers of aberrant
PI3K/mTOR signaling identified persistent HER3 tyrosine phosphorylation in a majority of HNCs. Importantly,
the anti-HER3 monoclonal antibody, CDX-3379, which blocks ligand-dependent and -independent functions of
both human and murine HER3 imparts potent antitumor activity in PIK3CA wild type HNC murine models and
patient-derived xenografts. Preliminary findings demonstrate that tumor rejection downstream from HER3
inhibition (HER3i) necessarily abolishes aberrant PI3K/mTOR signaling, polarizes the tumor microenvironment
towards anticancer immunosurveillance and is capable of achieving complete and durable rejection in our novel,
recently characterized murine, orthotopic model system of oral cavity, tobacco-signature HNC. My central
hypothesis is that HER3 inhibition will potentiate immune checkpoint blockade in HNC to achieve durable
response by disrupting PI3K/mTOR oncogenic signaling and reinstating effective cancer immunosurveillance.
My central premise is that this novel IO therapeutic platform can serve as the ideal model system in which to
explore fundamental tumor-immune dynamics in HNC and address questions regarding immune-escape and
resistance to immunotherapy. Additionally, I hypothesize that aberrations along the PI3K/mTOR signaling
pathway dictate the clinical relevance of aberrant HER3 signaling and regulate the sensitivity of HNCs to HER3
blockade. My premise here is that examination of the HER3-PI3K/mTOR-immune axis will inform predictions
regarding responsiveness to HER3i and identify novel therapeutic targets. To address this and achieve my
defined training goals that include broadening my experimental repertoire and expanding collaborative networks,
I specifically propose to examine responsiveness of HNCs to HERi by scrutinizing the PI3K/mTOR signaling
network and by characterizing fundamental tumor-immune interactions that drive tumor progression.

## Key facts

- **NIH application ID:** 10068468
- **Project number:** 1F32DE029990-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Robert Saddawi-Konefka
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $72,230
- **Award type:** 1
- **Project period:** 2020-06-28 → 2021-06-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068468

## Citation

> US National Institutes of Health, RePORTER application 10068468, Exploiting the HER3-PI3K/mTOR-Immune Axis to Design Precision Immune Oncology Therapy for Head & Neck Cancer (1F32DE029990-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10068468. Licensed CC0.

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