Combining Glutamine Metabolic Inhibitors with Carboplatin to Target MYC Amplified AT/RT
Background
Atypical teratoid rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy. Standard treatment involves intensive chemotherapy and radiation that causes severe morbidity but leads to a median survival of just six to 11 months. We are in dire need of new, targeted therapies to reduce side effects and improve survival. AT/RT has recently been divided into three sub-groups with different molecular drivers of tumor growth. In this proposal, we study a targeted therapy against a specific subgroup of AT/RT because we believe matching the right drug to the correct patient at the right time is crucial to improve survival in this deadly tumor. The subgroup of AT/RT with MYC expression is especially aggressive. MYC is known to drive cancer cell dependence on glutamine for energy needs. We have previously shown that MYC expressing AT/RT are especially sensitive to the glutamine metabolic inhibitor, 6-Diazo-5-oxo-L-norleucine (DON). Glutamine is essential for the production of glutathione which can bind to and inactivate platinum chemotherapies. High levels of glutathione in AT/RT may lead to drug resistance. We hypothesize that DON will sensitize AT/RT to the platinum agent, carboplatin by depleting intracellular glutathione.
Project Goal
In this proposal, we will test the impact of combining DON with carboplatin on cell proliferation and cell death. We will also develop murine models of AT/RT and test the impact of the combination of therapy on overall survival. At the completion of this proposal, we will have developed the pre-clinical justification for the first clinical trial that addresses the molecular heterogeneity recently discovered in AT/RT.
Mentored by Dr. Jeffrey Rubens
Johns Hopkins University School of Medicine, Baltimore, MD
