Dr. Paul B. Fisher, Professor and Chairman, Department of Human and Molecular Genetics, Director, VCU Institute of Molecular Medicine Thelma Newmeyer Corman Chair in Cancer Research in the VCU Massey Cancer Center, VCU, School of Medicine, Richmond, VA, and Emeritus Professor, Columbia University, College of Physicians & Surgeons, New York, NY. He published over 650 papers and reviews, is among the top NIH/NCI funded investigators and has 55 issued patents. He pioneered novel gene/discovery approaches, developed innovative therapeutic approaches, presented numerous named and distinguished lectures, founded several start-up companies, was Virginia Outstanding Scientist of 2014, and elected to the National Academy of Inventors in 2018. Dr. Fisher is a successful seasoned entrepreneur. He founded GenQuest Incorporated, a functional genomics company, which merged with Corixa Corporation in 1998, traded on NASDAQ and was acquired by GlaxoSmithKline in 2006. He co-founded (2017/2018) InVaMet Therapeutics (IVMT), developing small molecule inhibitors of metastasis, and InterLeukin Combinatorial Therapies (ILCT), moving therapeutic interleukins/cytokines from bench-to-bedside.
The primary cause of death in patients with advanced solid cancers involves spread and/or invasion in adjacent or distant organs, i.e., metastasis. Although extensively studied, prevention of metastasis and in the vast majority of cases effectively treating metastasis have not been successful. This highlights an
important and relevant question: Why is this aspect of the cancerous process so difficult to prevent and control? Metastasis can be defined by its many sequential steps- primary tumor proliferation (requires new blood vessels (angiogenesis), detachment/invasion into the circulatory system (intravasation),
survival in the circulatory system (embolism, resistance to stress), tumor cell adherence to the vessel wall at a secondary site, invasion into the secondary site (extravasation), the establishment of a microenvironment (modifying the tumor microenvironment (TME)) followed by proliferation and angiogenesis (formation of micro-metastases leading to macro-metastases). A reason for the failure of current therapies to be effective relates to the dynamic nature of cancer cell progression and the application of therapeutic strategies that can block one or at best only a few of these processes. Since at any point in time, cancer cells may present at different stages in the metastatic process, preventing and treating this ultimate stage of the cancerous process is a conundrum. Our approach to preventing and treating metastasis is to 1) identify critical players, genes, and proteins, controlling multiple steps in the metastatic cascade; 2) apply state of art chemistry approaches, such as fragment-based drug discovery (FBDD) informed by NMR, to identify small molecules that can inhibit the pro-metastatic gene(s)/protein(s); 3) evaluate the activity and elucidate mechanisms of action of the genes and proteins in vitro in cell culture and in vivo in animal models; 4) perform PK and ADME studies to identify potential drug-like molecules; 5) perform toxicology and if appropriate move the small molecule from “bench-to-bedside.” Using this development scheme, we identified melanoma differentiation-associated gene-9/Syntenin/Syndecan Binding Protein (mda-9) as a pro-metastatic gene/protein upregulated in multiple advanced cancers. MDA-9 is a scaffold protein that contains two PDZ domains and produces multiple effects on metastasis through interaction with other partner proteins. Our approach was able to identify specific inhibitors of this binding, including an inhibitor of the first PDZ domain (PDZ1i), that induced profound effects on the majority of stages of metastasis. PDZ1i is non-toxic but suppresses cancer cell invasion, and angiogenesis modifies the TME, potentiates immune activity toward the evolving cancer cells, and blocks metastasis in multiple animal models, including athymic nude mice, syngeneic mice, transgenic mice, and patient-derived PDX tumors. PK and ADME look promising, and we have developed a way of enhancing solubility leading to IND-enabling toxicology. Another property of PDZ1i is its ability to enhance the therapeutic efficacy of chemotherapy, radiation therapy, and immunotherapy. In summary, we have identified an inhibitor of potentially all of the major steps in the metastatic cascade, that is non-toxic and can both prevent and treat metastasis, enhanced when combined with a second therapeutic, originating from different histological tumors.