Charles L. Sawyers, MD

2009-2010 BCRF Project
Co-investigator: Lewis C. Cantley, PhD, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

Mutations in components of the PI3K pathway are among the most common across all cancers including breast cancer. It is crucial to annotate tumors for PIK3CA status as well as other members of the pathway in order to know their prognostic impact (i.e, do they define distinct subgroups with different outcome regardless of therapy?) as well as their correlation with response to PI3K pathway inhibitors. P53 mutations have been carefully studied in breast cancer, and are common, but their association with PIK3CA status is unknown. It will be important to know if they impact response to PI3K inhibitors. PTEN mutations are less common in breast cancer, but loss of protein expression is found in basal-like ("triple negative") breast cancers. The association of the gene INPP4B (which the Cantley group has recently shown can act as a tumor suppressor of PI3K signaling, analogous to PTEN) with breast cancer is less well studied but early data indicate loss of heterozygosity in basal-like breast cancer. Drs. Cantley and Sawyers will conduct the p53, PTEN and INPP4B sequencing analysis for mutations using the same DNAs previously characterized for PIK3CA status. They will also assess the copy number status of all three genes and will assess PTEN protein expression by immunohistochemistry.

Mid-Year Progress Report:
The purpose of this research is to identify mutations or deletions of genes that occur frequently in human breast cancers and to determine which investigational drugs are most potent at suppressing growth of breast cancer cell lines that have these same mutations. In addition the researchers will determine whether the drugs that are most effective in suppressing growth of the cell lines also suppress growth of tumors in genetically engineered laboratory models that have the same mutations as those found in human breast cancers. Their preliminary results show that a gene called INPP4B is frequently deleted in basal-like (triple-negative) breast cancers and that PI3K inhibitors that are currently in clinical trials inhibit growth of cancer cells in which INPP4B expression is impaired. These results suggest that PI3K inhibitors now in phase 1 clinical trials may be useful in treating basal-like breast cancers, such as those with BRCA1 mutations and INPP4B deletions.

Bio:
Dr. Sawyers is an Investigator of the Howard Hughes Medical Institute and the inaugural Director of the Human Oncology and Pathogenesis Program (HOPP) at Memorial Sloan Kettering Cancer Center, where he is building a program of lab-based translational researchers across various clinical disciplines and institutional infrastructure to enhance the application of global genomics tools to clinical trials.

Dr. Sawyers' laboratory is currently focused on characterizing signal transduction pathway abnormalities in prostate cancer, with an eye toward translational implications. His research is best demonstrated through his earlier studies of BCR-ABL tyrosine kinase function in chronic myeloid leukemia, his work with Brian Druker and Novartis in the development of the kinase inhibitor imatinib/Gleevec as primary therapy for CML, and his discovery that imatinib resistance is caused by BCR-ABL kinase domain mutations. This discovery led Dr. Sawyers to evaluate 2nd line Abl kinase inhibitors, such as the dual Src/Abl inhibitor dasatinib, which received fast track approval at the FDA in June 2006.

Dr. Sawyers' work in prostate cancer has defined critical signaling pathways for disease initiation and progression through studies in mouse models and human tissues. This preclinical work has led to the discovery of a novel antiandrogen MDV3100, a small molecule inhibitor discovered in collaboration with UCLA chemist Michael Jung, that targets the increased levels of androgen receptor found in hormone refractory disease. Based on impressive clinical results in a phase I/II study, MDV3100 is currently in a phase III registration trial.

Dr. Sawyers is past President of the American Society of Clinical Investigation and served on the National Cancer Institute’s Board of Scientific Councilors. He has won numerous honors and awards, including the Richard and Hinda Rosenthal Foundation Award and the Dorothy Landon Prize from the American Association of Cancer Research, the David A. Karnofsky Award from the American Society of Clinical Oncology and the 2009 Lasker~DeBakey Clinical Medical Research Award. He is a member of the Institute of Medicine of the National Academy of Sciences.