Targeting Glutamine Metabolism in MYC Driven Atypical Teratoid Rhabdoid Tumors
Atypical teratoid rhaboid tumors (AT/RT) are the most common brain tumors of infancy. Patients are currently treated with intensive chemotherapy and radiation that leads to severe side effects but few long-term survivors. We are in dire need of new, targeted therapies to treat these deadly tumors. Previous attempts at targeted therapies have treated AT/RT as a single entity but recent studies show that AT/RT are complex tumors with a range of molecular drivers of tumor growth. We propose the first targeted therapeutic strategy that addresses this molecular heterogeneity. MYC has been identified as one of the common drivers of AT/RT tumorigenicity. Like MYC driven neuroblastoma and medulloblastoma, this subclass of AT/RT consists of especially aggressive, deadly tumors. MYC is known to alter tumor metabolism to make tumors dependent on glutamine for creating energy. This reliance on glutamine may create an Achilles’ heel that can be targeted to improve survival.
In this proposal we aim to study how MYC expression sensitizes AT/RT to medications blocking glutamine metabolism. We will then determine the survival benefit of a novel glutamine antagonist with improved penetration into the brain. Finally we will look at resistance patterns that can help us identify further targeted therapies that can be paired with glutamine antagonists to further improve AT/RT survival. These studies will develop the preclinical rationale for future clinical studies aimed at improving our patient's lives suffering from these deadly tumors.