SPOTLIGHT: CBCRP-Funded Researcher Benjamin Cravatt
—Laurence Fitzgerald, Ph.D., CBCRP Biomedical Research Administrator
How can we attract investigators with the best new thinking and expertise to address the myriad unsolved research questions in breast cancer? The CBCRP has always offered innovative research award types as a beacon for new paradigms. Benjamin F. Cravatt III, Ph.D., a professor in The Skaggs Institute for Chemical Biology at The Scripps Research Institute, La Jolla, took up our challenge in 2000, when he was awarded two-year innovative grant funding to explore “Profiling Serine Protease Activities in Breast Cancer”. Dr. Cravatt's research group is interested in discovering new disease-associated protein biomarkers and therapeutic targets through proteomics. In proteomics, scientists survey the status of a large subset of cellular proteins in order to identify patterns of change specifically associated with cancer. As the Cravatt lab's Web site explains, “(the) focus of our lab is the development of chemical technologies for activity-based proteomics. The field of proteomics aims to characterize dynamics in protein function on a global scale.” The ultimate goal is the discovery and confirmation of new therapy targets for breast cancer.
In terms of a new approach to cancer biology, the Cravatt lab developed a proteomic technology, called Activity- Based Protein Profiling (ABPP). This allows them to simultaneously monitor the enzymatic activities of numerous serine proteases (i.e., proteins that cleave other proteins) from whole cell, tissue, and fluid samples. The goal of using ABPP is to discover the active proteases produced by breast cancer cells and tumor samples that are involved in cell motility and invasiveness. In actual practice, ABPP involves construction of small chemical probes that “interrogate” the status of enzyme active sites in complex protein mixtures from whole cells. Other methods of studying proteases have severe limitations, because many proteases are either made as inactive precursors or form complexes with inhibitors. Thus, just measuring protease gene activity (RNA abundance) or protease quantity does not equate to measuring enzyme activity. The key results of Dr. Cravatt's first CBCRP-funded project were published in the Proceedings of the National Academy of Sciences, USA 99:10335-40. They reported that cancer cells have discrete proteomic signatures that correlate with their invasive characteristics rather than with the type of cells they arose from (which is the traditional way of distinguishing tumors). This finding implies that there is a common set of enzymes that cause cells to become invasive and that these enzymes can serve as targets for diagnosing and treating cancer.
Of course, a promising discovery in cancer cell lines is still far removed from making a difference to breast cancer patients. The CBCRP awarded Ben Cravatt with additional funding in 2002 to extend the ABPP technology to study human tumors grown in animal models (xenografts). This grant is still in progress, but the results to date look promising. The final step will be to extend the ABPP approach to actual human tumor samples. For this, the CBCRP funded a two-year Translational Research Collaboration project in 2004. Dr. Cravatt is teaming up with Stefanie Jeffrey, M.D., Chief of Breast Surgery at the Stanford University School of Medicine. The aims for this new study are to expand the discovery and potential clinical relevance of novel breast cancer proteases closer to the patient setting. Dr. Jeffrey brings to the collaboration both clinical expertise and a cutting-edge background in breast cancer genetics. Using DNA microarray technology, developed at Stanford by David Botstein and Patrick Brown, the Stanford group established in 2000 that human breast cancers can be classified into five major subtypes based on their pattern of gene expression. The goal of the collaboration between Drs. Cravatt and Jeffrey is to use ABPP to determine the enzyme activity profiles of a panel of primary human breast tumors and correlate these proteomic data to key genetic and clinical parameters, including (1) gene expression profiles, (2) tumor type and grade, and (3) survival outcome. Eventual use of the ABPP technique in the treatment of human tumors is progressing because the ABPP detection probes can be developed into structural templates for designing inhibitory drugs to prevent breast cancer cell movement and tumor metastasis.
The story of the CBCRP's funding to Dr. Cravatt's lab and his progress illustrates the critical links between the Program priority of bringing researchers new to breast cancer into the field, exploring novel research paradigms, and encouraging collaboration and translation as an ultimate goal. As Dr. Cravatt states, “…the funding support from the CBCRP has given our group the very special opportunity to immerse ourselves in the field of breast cancer research. Considering that we had no previous research experience in breast cancer, it is highly unlikely that we would have obtained support from more traditional funding sources for our studies. Thus, by supporting our efforts to apply new and innovative methods to breast cancer research, the CBCRP has enabled us to make rapid and important advances (e.g., the discovery of new protein biomarkers for this disease) that would have been otherwise impossible to achieve. As a result of our interactions with the CBCRP, our group is now firmly committed to research in breast cancer, with multiple biological collaborations aimed at applying our technologies to discover new ways to diagnose and treat this disease.”
Dr. Cravatt received his undergraduate degree from Stanford University and his Ph.D. from The Scripps Research Institute where he has been on the faculty since 1996. He currently has 67 PubMed citations. Dr. Cravatt's lab is also supported by grants from the National Institutes of Health. The CBCRP also funded two postdoctoral fellows (Drs. Yongsheng Liu and Arul Joseph) and one graduate student (Nadim Jessani) in Dr. Cravatt's lab. He is a co-founder and on the Scientific Advisory Board of ActivX Biosciences Inc. in La Jolla. Besides oncology, the study of proteases has potential clinical applications in hematology, metabolic, and inflammatory diseases.
