Exploring novel approaches for the treatment of metastatic disease and elucidating the mechanisms that drive drug activation
Understanding the basic biology of drug dynamics is essential for improving cancer treatment. Our laboratory works to better understand drug activation and identify new delivery systems for anticancer drugs. We use a variety of pharmacologic approaches to evaluate the potential of new small molecules. This work is poised to improve outcomes for pediatric cancers patients.
Research in our laboratory focuses on the pharmacology of anticancer agents, and this work spans basic research from identification of novel drugs and mechanisms of drug activation to the generation of neural stem cells to act as tumor-specific delivery system for drug-activating enzymes. We anticipate that further development of these approaches and technologies will allow our team of molecular biologists and biochemists to improve the outcomes of children who are diagnosed with solid tumors.
Members of the BET family of epigenetic regulators are typically overexpressed in human tumors, driving alterations in transcription that contribute to oncogenesis. By developing inhibitors specific to particular domains in these proteins, we can increase the specificity and safety of these potential anti-cancer agents. Building on work initiated by former St. Jude faculty member Dr. Kip Guy, and in collaboration with Dr. Anang Shelat, we have identified and generated bromodomain-selective inhibitors for cancer therapy. This development was also the result of a unique collaboration with several senior faculty members at St. Jude who provided their expertise to efficiently take a tremendous amount of in vitro data and then conduct the necessary in vivo characterization to demonstrate the antitumor activity of the bromodomain compounds.
Our laboratory, in partnership with researchers at City of Hope, generated tumor-specific delivery systems for drug-activating enzymes using neural stem cells. When injected into a mouse model, neural stem cells home to and encapsulate tumors, suggesting they may be effective carriers for anti-cancer therapy. Additionally, neural stem cells offer a novel way to overcome traditional limitations including blood brain barrier impermeability and systemic toxicity. Subsequently, my lab explored how we could ‘load’ neural stem cells with drug-activating enzymes to enhance tumor-localized production of chemotherapeutic agents and increase targeted cytotoxicity. In collaboration with other senior St. Jude researchers, we developed numerous models to test and verify that the effectiveness of the approach. When combined with anticancer prodrugs, this methodology has demonstrated improved survival of animals bearing disseminated neuroblastoma. This therapeutic approach is now being tested in an adult clinical trial and, if successful, may drastically alter how we can target and treat metastatic diseases in patients.
Our laboratory studies the mechanism of drug activation by a class of enzymes called carboxylesterases. Using a combination of structural techniques, biochemistry, and medicinal chemistry, our team has identified irreversible inhibitors of these proteins. These compounds “lock” the carboxylesterases in a unique conformation, allowing us to identify domains within the enzymes that are responsible for a drug’s access to and exit from the active site. This understanding may lead to new drugs that are more efficiently activated by these proteins.
Dr. Philip M. Potter is a longstanding member of the St. Jude community, having completed a postdoctoral fellowship here after formal training at the University of Manchester and Paterson Institute for Cancer Research. Dr. Potter is constantly inspired by the resilience of the patients and families at St. Jude. He uses that motivation to ask the most challenging, paradigm shifting questions in the lab to discover new approaches for pediatric cancers. Dr. Potter draws on the expertise of colleagues and leverages the groundbreaking technologies available at St. Jude to exquisitely interrogate pharmacological phenomena and instruct the development of improved therapeutics.
Highly talented group of molecular biologists and biochemists with complementary expertise.