STL CURE
SARCOMA
Brian Andrew Van Tine, M.D., Ph.D. is a Professor of Medicine and Pediatrics at Washington University in St Louis, Missouri, where he is the Sarcoma Program Director at the Alvin J. Siteman Cancer Center. Dr. Van Tine received his Bachelor of Science degree from the Departments of Chemistry and Biochemistry at The University of Arizona in 1995. Dr. Van Tine completed his M.D. and Ph.D. degrees at the University of Alabama at Birmingham in 2005. His thesis research mainly focused on the role of Human Papilloma Virus (HPV) in the development of cervical cancer with Profs. Louis T. Chow and Thomas R. Broker. After completing his M.D., Ph.D., Dr. Van Tine came to Washington University in St. Louis/Barnes Jewish Hospital where he did his Internal Medicine Residency and Medical Oncology Fellowship. Working to understand the intricate chemical reactions of molecules occurring in various types of cancerous tumors for therapeutic translation into new drugs and treatments is the overall goal of the Van Tine laboratory.
Dr. Van Tine's Research
Dr. Van Tine’s laboratory identified a common defect in sarcoma; the loss of ASS1 (argininosuccinate synthetase 1) gene expression. Cells require arginine, an amino acid, to survive. A normal copy of the ASS1 gene is required to make the enzyme argininosuccinate synthetase 1, which helps make arginine in cells. His team is the first to report that this gene is silenced in ~90% of sarcomas. Sarcoma cancer cells are vulnerable to death if they are deprived of arginine and glutaminase, since they can’t make their own arginine due to this genetic mutation. His team identified the changes that occur when arginine is depleted from ASS1-deficient cells using global metabolomics, which investigates all of the chemicals in a cell sample. This led to identification of the first dual metabolic therapy for sarcoma using an enzyme that breaks down arginine and a glutaminase inhibitor.
In addition, his team identified that arginine starvation could be used to increase the transport of the chemotherapy drug gemcitabine via transporter protein SLC7A11, a concept currently being tested in a Phase II clinical trial (NCT03449901). The clinical trials associated with this research will lead to new treatments, transforming the clinical care of patients with sarcoma.
In parallel, Van Tine’s team is the first to identify 3-phosphoglycerate dehydrogenase (PHGDH), an enzyme that helps make the important amino acid serine out of glucose, as a therapeutic target in osteosarcoma. Too much PHGDH in osteosarcoma correlates with poor survival. Inhibiting PHGDH slows or stops osteosarcoma cell reproduction, but this leads to the activation of the pro-survival mTor pathway. Combining PHGDH inhibitors with mTor pathway inhibitors to eliminate the cancer cells could be the first dual or triple metabolism-based combination therapy for osteosarcoma.
Finally, the team has found that synovial sarcoma is missing a key protein, malic enzyme 1 (ME1), which forces synovial sarcoma tumors to rely on a different metabolic pathway. This makes it uniquely vulnerable to the inhibition of that alternate pathway. The drug ACXT-3102 interferes with this alternate route. The interference causes volatile waste to build up inside the cancer cells. When enough waste builds up inside, the cancer cells die.