# Targeting BCL-2 family-regulated cell death for HNSCC treatment

> **NIH NIH R03** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $77,625

## Abstract

Project Summary
The goal of this application is to demonstrate the feasibility of new combination treatments in several mouse
models of head and neck squamous cell carcinoma (HNSCC). The long-term prognosis of patients with
advanced HNSCC has shown little improvement over the last three decades. Induction chemotherapy with
platinum-based compounds (e.g. cisplatin) and epidermal growth factor receptor (EGFR)-targeted therapy with
cetuximab are the current chemotherapeutic treatments of choice for HNSCC, but the prolonged use of these
drugs is limited by their toxicity and by the development of resistance. Tumor cell death induced by both
conventional and targeted chemotherapy is often mediated by the BCL-2 family-dependent mitochondrial
apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are frequently mutated or
deleted in HNSCC rendering it refractory to treatment. To counter such resistance, direct therapeutic targeting
of the BCL-2 family is conceptually appealing. Our long-term goal is to develop novel strategies for HNSCC
treatment that directly target this intrinsic apoptotic pathway. We have investigated the cytotoxic effects of
cisplatin, which is used as standard therapy for locally advanced HNSCC. As preliminary data, we have
demonstrated that (1) The pro-apoptotic BCL-2 family protein Noxa is upregulated by cisplatin and is required
for cisplatin-induced apoptosis in a variety of HNSCC cells; (2) Noxa overexpression enhances cell death
induced by a pro-survival BCL-2/BCL-XL inhibitor, navitoclax (ABT-263) in HNSCC cells in vitro regardless of
p53 status; (3) Noxa can be induced by an endoplasmic reticulum (ER)-stress inducer, fenretinide (N-4-
hydroxyphenyl-retinamide). Using fenretinide as an alternative Noxa inducer, combination with fenretinide and
navitoclax efficiently induce cell death in HNSCC cells that are resistant to cisplatin. Based on the above
results, our central hypothesis is that simultaneous inhibition of MCL-1, BCL-XL, and BCL-2 is crucial for cell
death induction during HNSCC treatment. In order to test this hypothesis, we will determine the molecular
mechanisms of cisplatin + navitoclax or fenretinide + navitoclax activity in vitro (Aim 1). Furthermore, we will
define a new treatment modality by demonstrating the cytotoxic and overall therapeutic effects of cisplatin +
navitoclax or fenretinide + navitoclax combination in mouse models of HNSCC (Aim 2). The outcome of this
project will lead to development of alternative therapeutic strategies to directly modify the cell death machinery
in HNSCC.

## Key facts

- **NIH application ID:** 9964726
- **Project number:** 5R03CA235097-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Hisashi Harada
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $77,625
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964726

## Citation

> US National Institutes of Health, RePORTER application 9964726, Targeting BCL-2 family-regulated cell death for HNSCC treatment (5R03CA235097-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9964726. Licensed CC0.

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