Dr. Sawyers is an HHMI Investigator searching for molecularly targeted approaches to treat cancer. He has identified cell signaling components critical to the growth of cancer cells in chronic myeloid leukemia, prostate and other cancers, resulting in the development of multiple FDA-approved inhibitors in clinical use today.
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. We began this work in the context of chronic myeloid leukemia (CML), which is caused by the BCR-ABL fusion gene, also known as 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 then 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.
Prostate Cancer: Initiation, Progression and Mechanisms of Resistance
Buoyed by our success with BCR-ABL, we brought this approach to prostate cancer. For over a decade, our group has concentrated on defining the molecular basis of prostate cancer and mechanisms of resistance to hormone therapy. This work has 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, enzalutamide, that targets the increased levels of androgen receptor found in hormone refractory disease through a novel mechanism. This AR inhibitor was approved for use in men with castration-resistant prostate cancer in 2012. A second compound, apalutamide, was approved for use in 2018 to delay prostate cancer metastasis in certain at-risk patients.
Our current projects share the common goal of deciphering mechanisms of resistance to antiandrogen therapies and are grouped under the major themes of: crosstalk between AR and common molecular lesions in human prostate cancer (e.g. PTEN loss, TMPRSS2-ERG gene fusions and FOXA1 mutations); understanding AR structure and function; lineage plasticity in prostate tumors; and the prostate tumor microenvironment. We have developed several unique models to study prostate cancer initiation and progression, including genetically defined mouse models and primary prostate organoid culture. Our recent studies have focused on combining these tools with single cell analysis technologies to study genetic changes and tumor-host cell interactions in the prostate.
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.
Requests for Myc-CaP cell lines should be directed to ATCC. The order number at ATTC is Myc-CaP cell line (ATCC® CRL- 3255™).
About Charles Sawyers
Charles L. Sawyers received a BA from Princeton University in 1981 and an MD from Johns Hopkins University School of Medicine in 1985, followed by an internal medicine residency at the University of California, San Francisco. He became a Howard Hughes Medical Institute investigator in 2002 while at the University of California, Los Angeles, and then moved to Memorial Sloan Kettering in 2006, where he currently serves as the Chair of the Human Oncology and Pathogenesis Program.
Dr. Sawyers studies mechanisms of cancer drug resistance with an eye toward developing novel therapies. He co-discovered the antiandrogen drug enzalutamide that was approved by the FDA in 2012 for the treatment of advanced prostate cancer. He shared the 2009 Lasker~DeBakey Clinical Medical Research Award for the development of the ABL kinase inhibitor imatinib for patients with chronic myeloid leukemia and the second-generation ABL inhibitor dasatinib to overcome imatinib resistance. He received the 2013 Breakthrough Prize in Life Sciences, the 2013 Taubman Prize for Excellence in Translational Medical Science, the 2017 American Cancer Society (ACS) Medal of Honor for Clinical Research and the inaugural STAT Biomedical Innovation Award in 2019.
Dr. Sawyers is a member of the National Academy of Sciences, the National Academy of Medicine, and the American Academy of Arts and Sciences. He is past president of the American Association for Cancer Research (AACR) and the American Society of Clinical Investigation, was appointed to the National Cancer Advisory Board by President Obama and has served on the Board of Directors of Novartis since 2013. He also serves as Steering Committee Chair of AACR Project GENIE, an international consortium of cancer centers that share genomic and clinical data from patients treated at their respective clinical sites.
Dr. Sawyers serves on the Board of Directors of Novartis and is a co-founder of ORIC Pharm and co-inventor of enzalutamide and apalutamide. He is a science advisor to Agios Pharmaceuticals, BeiGene, Blueprint Medicines, The Column Group, Foghorn Therapeutics, Housey Pharmaceuticals, Nextech, KSQ Therapeutics, Petra Pharma Corporation, and PMV Pharma. He was a co- founder of Seragon Pharmaceuticals, purchased by Genentech/Roche in 2014.