ASS1 (Argininosuccinate Synthase 1) – The goal of this project is to characterize the metabolic response to arginine deprivation in sarcomas that lack argininosuccinate synthase 1 (ASS1), an enzyme that aids in endogenous arginine production, thus making these tumors arginine auxotrophic. We are trying to identify additional points of therapeutic intervention that induce a synthetic lethal response when targeting sarcoma tumors, in combination with arginine depletion using pegylated arginine deiminase (ADI-PEG20).
ME1 (Malic Enzyme 1) – Synovial Sarcoma (SS) is an aggressive malignancy with a bimodal age distribution and a high metastatic potential. SS accounts for approximately 10% of all soft tissue sarcomas. Currently, there are no FDA approved targeted therapies for SS. The primary focus of my research is identification and functional evaluation of metabolic dependencies in Synovial Sarcoma. We have identified aberrations in malic enzyme 1 (ME-1) expression in synovial sarcoma and other soft tissue sarcomas. ME1 catalyzes the oxidative decarboxylation of malate to generate pyruvate and CO2, producing NADPH from NADP+ in the process. NADPH is an essential reducing equivalent within the cell, providing electrons for reductive biosynthesis and recycling of cellular antioxidant systems. I am currently studying the metabolic consequences of variable ME1 expression in SS, specifically the effect on glutamine utilization and redox homeostasis. Understanding the cellular mechanisms that compensate for variable ME1 expression in SS and other cancers may identify metabolic dependencies that are therapeutically actionable.
PHGDH – Osteosarcoma is the most common type of primary malignant bone tumor. Current treatment regimens use high-dose methotrexate, which targets the folate pathway by inhibiting dihydrofolate reductase, as part of a pathway that converts serine to purines. We hypothesized that inhibition of PHGDH, the rate-limiting step in serine biosynthesis, would be active for the treatment of osteosarcoma, and are exploring methods of inhibiting the resulting survival pathways to develop novel therapies for osteosarcoma.
Lipids – Our lab has shown that many sarcomas deficient in ASS1 are able to evade cell death over time, even when treated with ADI-PEG20. This project focuses on understanding fatty acid metabolism by identifying lipid localization, recycling, and response of cells to inhibition of beta oxidation.