The main goal of our laboratory is the identification and characterization of signal transduction pathways that cause the dysregulation of growth and inhibition of apoptosis that characterize advanced human cancer. Our laboratory is dedicated to understanding the consequences of activation of these pathways and to using this information to develop mechanism-based therapeutic strategies.
A major focus is the evaluation of Hsp90 as a therapeutic target in cancer patients. Hsp90 is a cellular chaperone that is required for maintaining the proper conformation of several important signaling proteins, including transmembrane tyrosine kinases and steroid receptors. The laboratory is studying the role of Hsp90 family members in maintaining the transformed phenotype of cancer cells. The knowledge gained is being used to develop strategies for using Hsp90 inhibitors in patients. A lead compound, the ansamycin 17-AAG, is currently in clinical trial at MSKCC. The laboratory has developed, and is currently evaluating, second generation ansamycins and small-molecule inhibitors with potentially greater selectivity and more favorable pharmacologic properties. (See ansamycin and small-molecule inhibitor projects.)
In addition, the laboratory is studying kinase inhibitors that target EGFR, HER2, MEK, src, mTOR, Met, and small molecules that inhibit androgen receptor and estrogen receptor. These compounds are being used as re-agents to define the role of these pathways in tumor cells with the goal of developing strategies for using these agents in patients. (See kinase inhibitor project.)