David A. Sackler Professor of Pharmacology; Associate Cancer Center Director, Basic Science; Co-director, Cancer Biology Institute
PROJECT 1: Improved targeting of EGFR family members in squamous cell carcinomas of the head and neck
The epidermal growth factor receptor (EGFR) remains the only validated molecular target in head and neck squamous cell carcinoma (HNSCC), mediating cell survival signaling and resistance to radiation therapy. Despite the success of EGFR targeted therapies such as cetuximab, therapeutic resistance to EGFR targeting ultimately develops. A significant challenge for improving EGFR targeted therapies is to identify and clinically validate actionable mechanisms of therapeutic resistance.
In this proposal, we have designed a strategy that iterates between basic science investigations, preclinical testing, and clinical specimen testing to elucidate the mechanism of cetuximab resistance in HNSCC. Using an in vitro approach for analyzing cetuximab resistance, we identified upregulation of a targetable autocrine ligand, NRG-1, as a target mechanism of resistance. We have modeled this resistance both in cell lines and in vivo, using mouse xenograft studies, and have shown that it can be reversed therapeutically by using an ErbB3-targeted antibody therapeutic (CDX-3379) – which can restore responses to cetuximab and radiation therapy. We have also observed NRG-1-induced resistance to small molecule EGFR kinase inhibitors in cancer cells, and have studied the mechanistic origin of this resistance at a structural level. We propose to exploit this new knowledge to advance small molecular approaches for targeting EGFR family members in HNSCC.
In parallel with these studies, we will study clinical specimens from an ongoing phase II HNSCC trial of afatinib plus cetuximab, plus two ECOG trials of cetuximab, to investigate resistance mechanisms in the clinic. We will also develop patient-derived xenografts (PDX) models from the ongoing clinical trial to test hypotheses for resistance mechanisms and to assess effectiveness of new strategies devised to overcome it. The key premise of the proposal is that understanding mechanisms of resistance to cetuximab will open up new therapeutic opportunities – allowing us to develop approaches that can still inhibit EGFR when cetuximab fails, and to develop approaches to target other molecules that activate EGFR in a cetuximab-insensitive way (such as ErbB3).
Our three Specific Aims are:
- To elucidate and model mechanisms of cetuximab resistance in HNSCC, and to test CDX-3379 as a new ErbB3 targeted approach for enhancing systemic and/or radiation therapy in HNSCC.
- To develop new structure/mechanism-guided strategies for successful ErbB-receptor targeting with small molecule tyrosine kinase inhibitors (TKIs) in HNSCC.
- To identify biomarkers of therapeutic response to ErbB-targeted therapies using clinical trial samples, and to establish parallel patient-derived tumor models to evaluate mechanisms of resistance to ErbB-targeted therapies in HNSCC.
Project 1 Co-Leaders
Professor of Therapeutic Radiology and of Pharmacology; Co-Leader, Radiobiology and Radiotherapy, Yale Cancer Center; Vice Chair for Basic Science Research, Therapeutic Radiology; Chief, Central Nervous System Radiotherapy Program, Therapeutic Radiology