NMR of Melanoma Acidification, Bioenergetics, Metabolism and Therapeutic Response

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Melanoma is the most virulent of all the skin cancers. While often cured by early surgical excision, there is no generally effective method for treating disseminated disease. We propose to sensitize melanoma to cisplatin and cyclophosphamide utilizing a method for selective acidification of melanomas that we have recently developed. The basic strategy is to induce systemic hyperglycemia by i.v. infusion of glucose to maintain a vascular glucose concentration of 261 mM (465 mg/dL) to drive lactate production. To maximize tumor lactate production meta-iodobenzylguanidine (MIBG), an inhibitor of site-1 of the respiratory electron transport chain, is administered. Lactate is then trapped inside the tumor cells by administration of an inhibitor of the monocarboxylic acid transporter (MCT). In previous studies we have used α−CN-4-hydroxycinnamic acid (CNCn). By this method we have been able to maintain the intracellular pH (pHi) of DB1 melanoma xenografts at 6.2-6.4 for ~40 min.; the pHi of brain, liver and skeletal muscle were unaffected. Tumor levels of nucleoside triphosphates (NTP) decreased markedly, whereas the bioenergetics of muscle and brain were unaffected; the liver showed ~30% decrease in ATP. Since normal tissues do not exhibit a Warburg Effect, a therapeutic gain should result from this method. It is well known that the alkylating agents cisplatin and cyclophosphamide are activated in acidic media, thus, we anticipate that these drugs will be selectively activated in the tumor by selective metabolic tumor acidification. In Aim 1 we propose to adapt the selective metabolic acidification procedure to clinical translation by eliminating CNCn, which is not FDA approved, or replacing CNCn and with lonidamine, an agent that inhibits the MCT and also blocks oxidative phosphorylation by preventing pyruvate transfer into mitochondria. Lonidamine is widely used in the clinic in Europe, and the FDA has granted INDs for its use in the USA. Once the optimum selective acidification procedure is perfected on the DB1 tumor, we will determine if this method enhances the efficacy of cisplatin and cyclophosphamide against xenografts of this tumor in nude mice. Aim 2 will utilize histopathology, serum enzyme assays and a variety of functional tests utilizing our expertise in MRS and MRI as well as NIR optical redox scanning to examine the toxicity of these procedures to various critical normal tissues.