Professor, Thoracic Head & Neck Medical Oncology, MD Anderson Cancer Center
Location: United States
The research in my laboratory is directed at defining the biological and molecular effects of the modulation of signal transduction pathways in lung, head and neck, and HPV+ cancers. We have defined novel mechanisms of sensitivity and resistance to kinase inhibitors. The three main projects are:
We recently discovered that head and neck squamous cell carcinoma (HNSCC) tumors harboring NOTCH1 mutations were more sensitive to drugs targeting the PI3K/mTOR pathway than HNSCC cell lines with wild-type NOTCH1 receptors. Goals of this project are to: Determine the efficacy of PI3K/mTOR pathway inhibition in HNSCC patients with tumors that harbor inactivating NOTCH1 mutations; Elucidate the molecular mechanism underlying PI3K/mTOR dependency and sensitivity to drugs targeting this pathway in NOTCH1 mutant HNSCC; and Identify therapeutic targets that work in combination with PI3K/mTOR inhibitors to prevent resistance and maximize killing of NOTCH1 mutant HNSCC.
We published the first large-scale, integrated analysis to determine mechanisms of polo-like kinase 1 (PLK1) inhibitor-induced apoptosis in NSCLC by assessing gene/protein expression, gene mutation, and PLK1 inhibitor sensitivity. Mesenchymal NSCLC cell lines were more sensitive to PLK1 inhibitors than epithelial NSCLC. Indeed, inducing an epithelial phenotype increased resistance and inducing a mesenchymal phenotype increased sensitivity. We are investigating candidate pathways that underlie sensitivity to PLK inhibition.
A recently completed screen of 1122 compounds in HPV+ cancer cell lines identified clinically-relevant Aurora kinase inhibitors as effective drugs. Integrated analysis of genomics, proteomics, gene expression, and drug sensitivity has identified several candidate pathways of resistance that are currently being studied.
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