TMET-01. DISRUPTION OF THE SERINE-PRODUCING PATHWAYS SLOWS PROGRESSION OF THE SONIC HEDGEHOG-DRIVEN MEDULLOBLASTOMA

Abstract

Abstract We have found that medulloblastoma metabolism is specialized to promote growth in the CNS and can be targeted for anti-tumor therapy. Prior studies show that serine is scarce in the CNS and that metastatic tumors require serine-producing enzymes to grow in the brain. We analyzed whether medulloblastoma, a primary brain tumor, showed similar serine dependency. We found that Sonic Hedgehog signaling, which induces proliferation in cerebellar granule neuron progenitors in normal development and medulloblastoma formation when hyperactivated, also induces PHGDH and SHMT1, which each catalyze key steps in different serine-production pathways. To define the functional role of PHGDH and SHMT1 in medulloblastomas, we bred mice genetically engineered to develop SHH medulloblastomas with mice carrying deletions of each of these genes. We found that mice with Phgdh-deleted medulloblastomas showed slower progression and longer survival times, compared to mice with Phgdh-intact medulloblastomas. Medulloblastomas with combined deletion of Phgdh and Shmt1 show even slower tumor progression. Stable-isotope flux analysis suggests that different serine-producing pathways compensate for the loss of individual serine-producing enzymes, providing a rationale for the greater anti-tumor effect of disrupting multiple serine-producing enzymes simultaneously. Our data show that serine-producing enzymes can be targeted as a novel approach to medulloblastoma therapy, and underscore the importance of targeting multiple serine-production pathways in complex metabolic interventions.