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 on 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 aective 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.

Public Health Relevance

NMR of Melanoma Acidification, Bioenergetics, Metabolism and Therapeutic Response Project Narrative Melanoma, the most virulent form of skin cancer, is not responsive to chemotherapy. This project proposes to develop a method to sensitize melanomas to chemotherapy by selectively acidifying the cancer cells while minimally affecting normal cells. The method takes advantage of the fact that cancer cells prefer glucose as their primary source of energy and convert it to lactic acid.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129544-02
Application #
7847669
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Zhang, Huiming
Project Start
2009-05-21
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$466,922
Indirect Cost
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Nath, Kavindra; Nelson, David S; Roman, Jeffrey et al. (2017) Effect of Lonidamine on Systemic Therapy of DB-1 Human Melanoma Xenografts with Temozolomide. Anticancer Res 37:3413-3421
Nancolas, Bethany; Guo, Lili; Zhou, Rong et al. (2016) The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters. Biochem J 473:929-36
Shestov, Alexander A; Mancuso, Anthony; Lee, Seung-Cheol et al. (2016) Bonded Cumomer Analysis of Human Melanoma Metabolism Monitored by 13C NMR Spectroscopy of Perfused Tumor Cells. J Biol Chem 291:5157-71
Nath, Kavindra; Nelson, David S; Putt, Mary E et al. (2016) Comparison of the Lonidamine Potentiated Effect of Nitrogen Mustard Alkylating Agents on the Systemic Treatment of DB-1 Human Melanoma Xenografts in Mice. PLoS One 11:e0157125
Shestov, Alexander A; Lee, Seung-Cheol; Nath, Kavindra et al. (2016) (13)C MRS and LC-MS Flux Analysis of Tumor Intermediary Metabolism. Front Oncol 6:135
Nath, Kavindra; Guo, Lili; Nancolas, Bethany et al. (2016) Mechanism of antineoplastic activity of lonidamine. Biochim Biophys Acta 1866:151-162
Guo, Lili; Worth, Andrew J; Mesaros, Clementina et al. (2016) Diisopropylethylamine/hexafluoroisopropanol-mediated ion-pairing ultra-high-performance liquid chromatography/mass spectrometry for phosphate and carboxylate metabolite analysis: utility for studying cellular metabolism. Rapid Commun Mass Spectrom 30:1835-45
Guo, Lili; Shestov, Alexander A; Worth, Andrew J et al. (2016) Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine. J Biol Chem 291:42-57
Nath, Kavindra; Nelson, David S; Heitjan, Daniel F et al. (2015) Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin. NMR Biomed 28:281-90
Nath, Kavindra; Nelson, David S; Heitjan, Daniel F et al. (2015) Effects of hyperglycemia on lonidamine-induced acidification and de-energization of human melanoma xenografts and sensitization to melphalan. NMR Biomed 28:395-403

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