Dr. Rubin Grandis’ research program is dedicated to increasing our understanding of the genetic alterations in the upper aerodigestive tract mucosa, which result in head and neck squamous cell carcinoma. The overall goal is to identify pathways that can serve as therapeutic targets for novel preventive or treatment strategies. We are studying signaling pathways regulated by the epidermal growth factor receptor (EGFR), stimulated by direct activation (EGFR ligand) and indirect activation (G-protein-coupled receptor ligand). Cumulative evidence from our lab today suggests that TGF-a/EGFR autocrine signaling is activated early in head and neck carcinogenesis where expression levels of ligand or receptor are important prognostic indicators in head and neck cancer patients. Strategies aimed at blocking the ligand or receptor demonstrated anti-tumor efficacy in preclinical models. Based on these promising results, we have initiated a Phase I clinical trial to investigate the toxicity and biologic effects of EGFR antisense gene therapy.
Further studies are aimed at elucidating the molecular mechanisms underlying the TGF- a/EGFR autocrine regulatory pathway. These studies have demonstrated mitogenic signaling as a result of EGFR-mediated activation of selective STAT proteins including Stat3 and Stat5b in head and neck cancer cells. Current projects are investigating strategies to block activated Stat3 and/or Stat5b for potential use as cancer therapy. In summary, our translation research efforts are dedicated to elucidating the critical growth pathways in head and neck cancer progression. By characterizing cell lines and patient tissues, followed by examination of mitogenic signaling mechanisms in preclinical animal models, we hope to develop innovative approaches to preventing and treating this frequently fatal malignancy.
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