Although to date, few randomized phase III melanoma trials have shown clinical benefit, post hoc analysis of some trials, which buy inhibitor overall were negative, did reveal statistically significant benefits in favor of the inves tigational arm for melanoma patients with normal versus high serum LDH. The SYMMETRY study, a randomized phase III trial that determined efficacy of the small molecule inhibitor Elesclomol, administered alone or in combination with paclitaxel, provided evidence that while the combination of Elesclomol with paclitaxel led to significant progression free survival in patients with normal serum LDH, there was a trend towards worse overall survival in patients with high serum LDH. We and others have shown that Elesclomol suppresses OXPHOS in melanoma cells in vitro, and that melanoma cells without mitochondrial DNA are more resistant to low to moderate doses of Elesclomol.
These findings, in addition to the critical role of LDH in the interconversion of lactate and pyruvate in the production of ATP through glycolysis or OXPHOS, prompted us to hypothesize that Inhibitors,Modulators,Libraries differences in serum LDH among patients with metastatic melanoma reflect differential dependence Inhibitors,Modulators,Libraries upon these bioenergetic pathways. In view of these observations we sought to determine whether 1) the LDH isoform expression profile and levels of lactate in serum obtained from up to 49 patients with metastatic melanoma would correlate with disease progression and OS. and 2) whether melanoma development and progression might be linked with key enzymes in glycolysis, OXPHOS, and lactate transport.
Our data presented herein demonstrate that patients with advanced metastatic melanoma and high serum LDH have low levels of LDH1 and LDH2, but elevated levels of LDH3 and 4, suggesting that glycolysis is the primary metabolic pathway utilized by the tumor cells in Inhibitors,Modulators,Libraries these patients. In contrast, in patients with advanced melanoma and normal serum LDH, OXPHOS has an important role in addition to glycolysis for energy production. Furthermore, our data demonstrate that several key enzymes associated with high OXPHOS are substantially elevated in primary and metastatic melanomas compared with nevic melanocytes. Together these findings support a model that both glycolysis and OXPHOS play a significant role in developing metabolic symbiosis in metastatic melanoma progression.
Materials and methods Inhibitors,Modulators,Libraries Patient sera, melanoma cell lines, and tumor cell suspensions Sera from patients with stage IV metastatic melanoma were obtained in compliance with University of Pittsburgh Cancer Institute protocols 96 099 and 11 108. Overall Inhibitors,Modulators,Libraries survival was defined as the interval from collection of serum LDH, LDH isoenzyme, and serum thereby lactate to death from any cause. Human epidermal melanocytes were propagated in melanocyte growth medium.