Targeting Glucose Metabolism in Medulloblastoma

Abstract

Medulloblastoma is the most common malignant brain tumor of childhood. Although current treatment approaches for this cancer have improved overall survival, they leave devastating and lifelong sequelae and the mortality remains high. Novel targeted therapies are therefore crucial to improve survival in these children and decrease treatment‐related toxicity.Medulloblastoma development is largely driven by deregulation of normal cerebellar proliferation wherein the sonic hedgehog (Shh) pathway plays a critical role. Activating mutations of Shh genes are frequent in medulloblastoma and promote their rapid growth. In addition, highly aggressive Shh‐active medulloblastomas also exhibit mutations of the Ras/MAPK pathway and increased HIF‐1α, which are observed to stimulate glycolysis by activating the 6‐phosphofructo‐2‐kinase/fructose‐2,6 bisphosphatase family of enzymes (PFKFB1‐4). The PFKFBs produce fructose‐2,6‐bisphosphate (F26BP), a potent activator of 6‐phosphofructo‐1‐kinase, a rate‐limiting step in glycolysis. Recent data indicate that the PFKFB4 family member is increased in multiple human tumors and cancer lines, required for cell survival in aggressive brain tumors and strongly induced by hypoxia. We have found that the PFKFB4 enzyme was highly expressed in a series of patient‐derived medulloblastomas and correlated significantly with expression of the Shh pathway effector Smoothened (SMO) and GLI1. Through HIF‐1α upregulation, hypoxia was observed to strongly induce PFKFB4 expression in Shh‐active medulloblastoma cells and silencing PFKFB4 in these cells markedly suppressed F26BP and glycolytic flux to lactate and significantly decreased cell survival and proliferation, more prominently in hypoxia, indicating that PFKFB4 may be preferentially required for survival and growth under hypoxia. In addition, we found that co‐silencing PFKFB4 with SMO or GLI1 markedly decreased cell survival. We have recently developed a novel selective small molecule inhibitor of PFKFB4 and examined the effects of inhibiting PFKFB4 and the Shh pathway simultaneously. We found that simultaneous administration of the PFKFB4 inhibitor and inhibitors of the Shh pathway synergistically decreased Shh‐active medulloblastoma cell viability. Taken together, our data indicate that targeting PFKFB4 may be a valid therapeutic option against medulloblastoma and strongly support the further examination of simultaneous inhibition of PFKFB4 and the Shh pathway as a treatment strategy in medulloblastoma.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.