Metabolic rewiring in cancer Targeting metabolic vulnerability for therapy

Metabolic reprogramming is one of the hallmarks of cancer and recaptured the attention of researchers in the past decade. The discovery of isocitrate dehydrogenase 1 and 2 mutations (IDHMUT) in cancer has unveiled dysregulated metabolism and cellular energetics in terms of their biological importance related to oncogenesis. IDHMUT occur in various types of cancers such as glioma, cholangiocarcinoma, chondrosarcoma and acute myeloid leukemia. This thesis discusses the role of IDHMUT in cancer- inducing alterations in metabolism and the production of the neomorphic metabolite D-2- hydroxyglutarate (D-2HG) and its consequences on the biological and molecular level for cellular metabolism. A major finding was that IDH1WT glioma showed a typical glycolytic lactate production whereas in IDH1MUT glioma metabolism is driven by lactate and glutamate to facilitate production of D-2HG. This important finding indicates that not glutaminolysis but glutamatolysis should be the target for therapy. In addition, therapy sensitivity of IDHMUT cancers and the association with prolonged survival of patients with IDH1MUT is discussed. It appeared that both a reduced NADPH production capacity and an oxidative metabolic phenotype is involved in radio- and chemosensitivity in IDH1MUT cancer cells. With the insights of the vulnerabilities of IDH1MUT cancer cells we provided data involving hyperthermia in multimodality treatment of patients with IDHMUT solid cancers in addition to conventional treatment like irradiation and/or chemotherapy. A clinical trial is performed using the oral antidiabetic drug metformin and the oral antimalarial drug chloroquine to disrupt the vulnerable metabolism of IDHMUT solid tumors including chondrosarcoma, glioma and intrahepatic cholangiocarcinoma.