Mark M. Moasser, MD
Professor in Residence
Department of Medicine
Member, Helen Diller Family Comprehensive Cancer Center
University of California, San Francisco, San Francisco, California
2013-2014 BCRF Project:
(American Association for Cancer Research)
Approximately 20-25% of breast cancers are driven by over-activity of the HER2 oncogene, which is commonly referred to as the HER2 positive subtype of breast cancer. There is a great deal of scientific evidence that this type of cancer can be highly effectively treated, maybe even eradicated, through the development of drugs that can effectively inactivate the function of HER2. This has been the motivation underlying the development of a number of HER2-targeting drugs including trastuzumab (Herceptin®), pertuzumab (Perjeta®), lapatinib (Tykerb®), and T-DM1 (Kadcyla®). These drugs have shown clinical efficacy and are approved for use. However, their efficacy is modest because they only minimally affect HER2 function. But their modest clinical activity is encouraging for future endeavors to develop drugs that completely inactivate HER2 function. Dr. Moasser’s BCRF-funded project concerns such a next generation approach seeking to fully inactivate HER2.
Dr. Moasser’s approach has to do with the exquisite dependency of HER2 on the chaperone protein HSP90. There are many inhibitors of HSP90 available, and such inhibitors lead to the near-complete degradation of the HER2 protein. In cell culture, this very effectively kills HER2-positive breast cancer cells. The problem is that HSP90 is important for almost 1,000 other cellular proteins, not just HER2, and therefore such inhibitors are very toxic for clinical use, and they cannot be given to patients at sufficient dosing to degrade the HER2 in their cancers.
Dr. Moasser has been studying how HSP90 supports the stability of its diverse protein clients and believe it is possible to develop drugs that interfere with HSP90-HER2 interaction specifically, sparing all the other hsp90 clients. This requires developing an in-depth understanding of how HSP 90 and HER2 come together. In the past year, Dr. Moasser’s group has made considerable progress in this regard. They have been improving the methodologies and resolution of cryoelectron microscopy using new camera technologies and biochemical methods to stabilize and align the proteins better. They are getting close to the resolution which will allow mapping the HER2-HSP90 interface. They have also been making substantial progress in screening for small molecules (potential predecessors of future drugs) that could affect specific (not all) functions of HSP90. They have established the assay system and have begun screening a large library of small molecules.
The hope is that this work will lead to a new generation of drugs that are much more clinically active for the treatment of HER2-positive (HER2+) breast cancers, which can potentially put even patients with advanced stage HER2-positive breast cancer in a complete remission from disease.
Dr. Mark Moasser runs a translational cancer research program focused on translating current understanding of tyrosine kinase signaling in epithelial cancers into better treatments for patients with cancer. His background includes clinical training in medical oncology and 16 years in the clinical practice of breast oncology, as well as several years of post-doctoral scientific training and 10 years as an independent investigator. Dr. Moasser’s hybrid clinical and scientific training have given his the background necessary to pursue translational research in both directions: pursuing clinically relevant scientific questions at the bench, and translating scientific discoveries into clinical trials. Dr. Moasser has a track record of several clinical trials emerging directly from his laboratory discoveries.