Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Children with high-risk and recurrent neuroblastoma have poor survival rates, and novel therapies are needed. Many cancer cells have been found to preferentially employ the glycolytic pathway for energy generation, even in the presence of oxygen. 3-BrOP is a novel inhibitor of glycolysis, and has demonstrated efficacy against a wide range of tumor types. To determine whether human neuroblastoma cells are susceptible to glycolysis inhibition, we evaluated the role of 3-BrOP in neuroblastoma model systems. Neuroblastoma tumor cell lines demonstrated high rates of lactate accumulation and low rates of oxygen consumption, suggesting a potential susceptibility to inhibitors of glycolysis. In all ten human tested neuroblastoma tumor cell lines, 3-BrOP induced cell death via apoptosis in a dose and time dependent manner. Furthermore, 3-BrOP-induced depletion of ATP levels correlated with decreased neuroblastoma cell viability. In a mouse neuroblastoma xenograft model, glycolysis inhibition with 3-BrOP demonstrated significantly reduced final tumor weight. In neuroblastoma tumor cells, treatment with 3-BrOP induced mTOR activation, and the combination of 3-BrOP and mTOR inhibition with rapamycin demonstrated synergistic efficacy. Based on these results, neuroblastoma tumor cells are sensitive to treatment with inhibitors of glycolysis, and the demonstrated synergy with rapamycin suggests that the combination of glycolysis and mTOR inhibitors represents a novel therapeutic approach for neuroblastoma that warrants further investigation.
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PMID:The combination of the novel glycolysis inhibitor 3-BrOP and rapamycin is effective against neuroblastoma. 2089 Jul 85

Estimated 5-year survival rates for patients with non-high-risk and high-risk neuroblastoma are 90% and 50%, respectively. Recent clinical trials have shown excellent outcomes with reduced therapy for non-high-risk disease. For patients with high-risk neuroblastoma treated with chemoradiotherapy, surgery, and stem cell transplantation, the addition of anti-disialoganglioside (GD2) immunotherapy plus cytokines improves survival. Upcoming trials will study the incorporation of targeted radionuclide therapy prior to myeloablative chemotherapy into high-risk treatment. Phase 2 trials will investigate druggable target(s) including mTOR inhibition and GD2-directed therapy in combination with chemotherapy for patients with recurrent neuroblastoma, and ALK inhibition for those with ALK-aberrant tumors.
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PMID:Children's Oncology Group's 2013 blueprint for research: neuroblastoma. 2325 19