Overcoming Resistance to Molecularly Targeted Cancer Therapy
Our laboratory is focused on characterizing signal transduction pathway abnormalities in various cancers with an eye toward translational implications. One example is chronic myeloid leukemia (CML) which is caused by the BCR-ABL fusion gene, expressed as a consequence of the Philadelphia chromosome translocation. In collaboration with Brian Druker at Oregon Health Sciences University, we developed the ABL kinase inhibitor imatinib/Gleevec as primary therapy for patients with CML. Shortly thereafter, my group discovered that resistance to imatinib is caused by BCR-ABL kinase domain mutations. We worked closely with John Kuriyan's group to examine the structural consequences of these mutations on the ABL kinase domain and postulated that second generation ABL kinase inhibitors that bind to ABL differently from imatinib might retain activity against imatinib-resistant mutants. In collaboration with scientists at Bristol Myers Squibb, we showed that the dual Src/Abl inhibitor dasatinib has such properties in preclinical models, then co-led the clinical development of dasatinib as treatment for imatinib-resistant CML. Subsequently, we found that dasatinib resistance occurs through additional, novel BCR-ABL mutations, some of which remain sensitive to imatinib, making a strong case for combined ABL kinase inhibitor treatment to prevent the emergence of resistant subclones.
A second project in my group explores the molecular basis of prostate cancer and mechanisms of resistance to hormone therapy. This work is currently focused on the role of the androgen receptor in disease progression, even when tumors progress to the hormone-refractory stage. After demonstrating that higher levels of androgen receptor are necessary and sufficient to confer resistance to current antiandrogens, we collaborated with UCLA chemist Michael Jung to discover a small molecule inhibitor that targets the increased levels of androgen receptor found in hormone refractory disease by a novel mechanism. A phase I-II trial of this compound (MDV3100), now underway at MSKCC and other sites, has shown impressive clinical responses in men with castrate-resistant prostate cancer, including those who have progressed on chemotherapy. MDV3100 will undergo phase III clinical testing beginning in 2009. Current projects are deciphering mechanisms of resistance to MDV3100, dissecting AR function using RNA interference screens and examining crosstalk between AR and other common molecular lesions in human prostate cancer such as PTEN loss and TMPRSS2-ERG gene fusions.
Requests for LAPC4 or LAPC9 cells should be directed to Dr. Robert Reiter at UCLA. For further information, contact his lab manager, Joyce Yamashiro at JYamashiro@mednet.ucla.edu
About Charles Sawyers
Dr. Sawyers is President of the American Association for Cancer Research and was recently appointed by President Obama to the National Cancer Advisory Board. He is past President of the American Society of Clinical Investigation, and serves on the National Cancer Institute's Board of Scientific Counselors. He is also a Member of the Institute of Medicine of the National Academy of Sciences.
Dr. Sawyers has received numerous accolades, including the AACR-Richard & Hinda Rosenthal Foundation Award, the Dorothy P. Landon-AACR Prize for Translational Cancer Research, the Doris Duke Distinguished Clinical Scientist Award, the American Society of Clinical Oncology David A. Karnofsky Award, and most recently the Breakthrough Prize in Life Sciences and the 2013 American Cancer Society/Society of Surgical Oncology Basic Science Lecture.