Charles L. Sawyers, MD

2011-2012 BCRF Project:
Co-Investigators: Lewis C. Cantley, PhD and Gerburg Wulf, MD, PhD, Beth Israel Deaconess Medical Center, Boston, MA

Metastatic, hormone-refractory breast cancer remains an incurable illness. Currently used chemotherapy regimens will delay, but not cure, metastatic disease. Newer agents that target the genetic mutations that tumor cells harbor have proven effective to delay the progression of the disease, but as single agents, they have not proven curative. In this research team's first year of funding, Drs. Cantley, Wulf, and Sawyers found several combinations of a new class of drugs called PI3Kinase-inhibitors with other targeted agents that delayed tumor progression in a laboratory model of aggressive breast cancer, and in some instances even led to remission of the cancer. They have evidence that these drugs can also impact response to hormone therapies.

Building on their previous work, this research team in 2011-2012 proposes to examine the efficacy and mechanisms of action of combination treatments that include PI3Kinase inhibitors for endocrine-resistant breast cancer. Some breast cancer cells have been observed to be "resistant" or do not respond to endocrine therapy; therefore, combining endocrine therapy with PI3Kinase inhibitors should enhance the effectiveness of therapies for women with endocrine-resistant breast cancer.

Mid-year Progress: Metastatic triple negative breast cancer (TNBC), a form of hormone-refractory breast cancer, is currently treated with chemotherapy, but the results are often marred by toxicity and the inability to achieve a cure. Therefore, there is an urgent need to develop treatments that are more specific and less toxic to improve outcomes for women with TNBC. While the development of estrogen receptor blockers and trastuzumab (Herceptin®) were major breakthroughs for estrogen receptor positive (ER+) and HER2+ breast cancer, a similar, specific target in TNBC has thus far remained elusive. Blockade of growth factor receptors similar to HER2 has remained ineffective, largely because cancer cells can evade such blockade by re-routing their growth signaling through alternate pathways.

In their work, Drs. Cantley, Sawyers, and Wulf have demonstrated that triple negative breast cancer cells can be attacked by disabling the enzyme PI3Kinase, which affects cancer cell growth control. PI3Kinase carries the signals that emanate from growth factors and other signals that stimulate the survival and division of cancer cells. In their preliminary studies, this research team has shown that blockade of PI3Kinase stops cancer cell division and starves these cells in a way that can eventually lead to cell death. Previously, they had also shown that activation of the PI3Kinase pathway in TNBC is a specific event that occurs as the result of either loss or gain of genes that regulate its activity. Therefore, it is the team's hypothesis that therapeutic targeting of PI3Kinase may be both effective and well tolerated. The investigators have discovered a surprising synergy of PI3Kinaseinhibition with PARP-inhibition in a laboratory model of BRCA1-related breast cancer and based on these data they anticipate the opening of an early phase clinical study at multiple institutions including the Dana-Farber/Harvard Cancer Center and Memorial Sloan Kettering Cancer Center in mid-2012.

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's 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's 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.