The goals of our Phase 1 research program at MSKCC are to: 1) identify promising new therapeutic agents;2) preclinical study of these agents to better understand the mechanism of action of these agents;3) extension of preclinical data into rational patient-oriented clinical trials through dose-finding (Phase I) single agent or combination trials;and 4) identification of innovative approaches to Phase 1 study conduct using novel biostatistical, pharmacokinetic, and pharmacodynamic approaches. A close collaboration between laboratory and clinical scientists are required to accomplish these goals. We will focus on projects as illustrative of the lab-to-clinic translational research at MSKCC: (1) Hsp90 is an abundant cellular chaperone that is required for refolding of unfolded proteins and we have demonstrated that inhibition of Hsp90 induces the rapid degradation of HER2 and loss of its expression on the membrane. We took advantage of this unique property of Hsp90 inhibitors and developed a novel non-invasive method for imaging loss of HER2 expression in the tumors. This molecular imaging approach will provide a platform for in vivo testing of HspQO inhibitors in patients;(2) Cytotoxic chemotherapy continues to be the mainstay of treatment for many cancers. Since most conventional anti-cancer agents impart damage to the genome and therefore also activate cell cycle checkpoints, pharmacological disruption of collateral checkpoint pathways might create 'synthetic lethality'selectively in tumors and represent a significant therapeutic opportunity;the basic understanding of the targets and sequence of treatment is necessary for our clinical study design;(3) Epidermal growth factor tyrosine kinase inhibitors (EGFR TKIS) such as gefitinib and erlotinib have changed how we treat non-small lung cancers. Certain EGFR kinase domain mutations underlie dramatic sensitivity to EGFR TKIS but we have shown that acquired resistance to EGFR TKIS invariably occurs and is often associated with the T790M resistance mutation of EGFR and represents a significant problem for patients with lung cancer. Further understanding of the mechanisms underlying this process will facilitate ways to both to both overcome and suppress the development of acquired resistance. These projects focus our effort on building strong bench-to-bedside and back-to-bench research. This iterative research approach to develop novel targeted therapy is critical to our success in the fight against cancer.
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