Biography
Dr. Sawyers is Professor of Medicine and Director of the Prostate Cancer Program Area at the UCLA Jonsson Comprehensive Cancer. He is a member of the UCLA Molecular Biology Institute and a practicing oncologist in the UCLA prostate cancer clinic. Dr. Sawyers is well-known in leukemia circles for his work on the BCR-ABL tyrosine kinase in chronic myelogenous leukemia. He was a primary participant in the design and conduct of clinical trials of the ABL tyrosine kinase inhibitor STI571 (Gleevec), and his lab was the first to identify mechanisms of drug resistance due to Bcr-Abl gene mutation and amplification. He has also applied his expertise in signal transduction to human prostate cancer. His group has developed a novel set of human prostate cancer xenografts which have allowed molecular biological investigations into the mechanisms of hormone-refractory prostate cancer progression and metastasis. Most recently his laboratory has implicated deregulation of the PTEN/AKT pathway as a major event in advanced prostate cancer.
Dr. Sawyers received his undergraduate degree from Princeton University and his medical degree from the Johns Hopkins School of Medicine. He completed a residency in Internal Medicine at the UCSF Medical Center, and a clinical fellowship in Hematology/Oncology at the UCLA School of Medicine. He also completed a post-doctoral fellowship in Molecular Biology at the UCLA School of Medicine. Dr. Sawyers is board certified in Internal Medicine, Medical Oncology, and Hematology. He has published over 60 scientific and medical papers in such journals as the New England Journal of Medicine, Science and Cell. Dr. Sawyers has won numerous honors and awards, including the Franklin D. Murphy Prize, Stohlman Scholar of the Leukemia and Lymphoma Society, and he was recently appointed the Peter Bing Professor at the UCLA School of Medicine.
Abstract
Kinase Inhibitor Therapy for Cancers with Aberrant PTEN/Akt Pathway Signaling
My research has focused on characterizing signal transduction pathway abnormalities in human cancers—first in chronic myeloid leukemia (CML) and now in prostate cancer. In addition, I have first hand experience in clinical research, through the design and conduct of the phase I-II trials of STI-571 in CML in collaboration with Brian Druker. Most recently, I have linked these two aspects of my career by showing that resistance to STI-571 can occur through Bcr-Abl gene amplification or mutation. In addition, to teaching us about CML and kinase inhibitor therapy, this work clearly demonstrates the value of molecular target analysis in patients treated with signal transduction inhibitors. Several years ago, my lab demonstrated that the PTEN/Akt pathway is dysregulated in up to 50 percent of men with advanced prostate cancer. We and others have demonstrated that aberrant signaling through this pathway is sufficient to cause prostate cancer (and other cancers) in mouse models. Now we have pre-clinical evidence that an inhibitor of the mTOR kinase, which is a downstream component of the PTEN/Akt pathway, is effective treatment for prostate cancers and gioblastomas with PTEN/Akt pathway abnormalities. One mTOR inhibitor (CCI-779) has completed phase I safety testing and is well tolerated at doses above that required to inhibit mTOR. My goal for the Doris Duke award is to apply the STI-571/CML model for developing kinase inhibitor therapy to cancers in which the PTEN/Akt pathway signaling is dysregulated. We will develop the appropriate molecular assays to identify cancers with perturbations in the PTEN/Akt pathway and conduct clinical trials of CCI-779 in these patients.