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  • Preliminary results of studies sponsored by the manufacturer

    2024-05-25

    Preliminary results of studies sponsored by the manufacturer of ETC-1002 have also shown positive results for monotherapy in statin-intolerant patients and for the combined use of the ACL inhibitor plus other cholesterol-reducing agents. In patients with a documented history of intolerance to statins, ETC-1002 60 to 240 mg/d has reduced plasma LDL-C up to 32%. Addition of the new agent in the same dose range to 10 mg/d of atorvastatin has provided an additional LDL-C reduction of up to 22%. Similarly, combined use with ezetimibe 10 mg/d has lowered LDL-C levels up to 48% (180 mg of ETC-1002 plus 10 mg of ezetimibe), an effect similar to that obtained with substantial doses of most available statins. In all clinical studies undertaken so far, the rate of adverse effects and/or discontinuation in the ETC-1002 treatment groups has been equal to or lower than that in the placebo group of each study. This was also true in the patients with a documented history of intolerance to statins, suggesting that muscle-related adverse events are not necessarily a direct consequence of reductions in LDL-C, but instead an effect related to other properties of statins as a pharmacologic group. Treatment with ETC-1002 has not increased plasma levels of liver transaminases, creatine kinase, bilirubin, or creatinine (Table 2).
    Conclusions
    Acknowledgments
    Melanoma is the most life-threatening skin cancer for its rapid progression and frequent resistance to BRAF/MEK inhibitors. Enhanced lipogenesis and mitochondria function are two hallmark metabolic characteristics of melanoma, but their crosstalk in regulating melanoma growth and MAPK inhibitors resistance has not been elucidated. ATP-citrate lyase (ACLY) is a critical enzyme in lipogenesis by producing acetyl-CoA, the building block for fatty SGC-CBP30 australia synthesis. Herein, we first found that ACLY expression was significantly increased in melanoma and highly correlated with poor clinical outcomes. Then, the knockdown of ACLY markedly attenuated cell proliferation and suppressed tumor growth . Subsequently, through the genome-wide mRNA profile analysis, we found that ACLY specifically regulated the expression of melanocytic lineage transcription factor MITF and its downstream PGC1α. The oncogenic role of ACLY was dependent on mitochondrial oxidative phosphorylation mediated by MITF-PGC1α axis. More importantly, ACLY conferred resistance to BRAF/MEK inhibitors by potentiating MITF-PGC1α axis and mitochondria function, and the combination treatment with ACLY inhibitor sensitized BRAF mutant melanoma to MAPK inhibition. Further mechanistic study revealed that ACLY regulated acetyltransferase P300 activity, increasing the histone acetylation at the MITF locus, thus activating MITF transcription and mitochondria biogenesis. Altogether, our results demonstrate that ACLY contributes to melanoma growth and MAPK inhibitors resistance by epigenetically regulating MITF and oxidative phosphorylation, providing a novel linkage between lipid metabolism and mitochondria function in tumor biology.
    Introduction Next to glucose, leucine is the most potent physiological insulin secretagogue and it is the only amino acid that supports insulin secretion in the absence of glucose or another amino acid. One of the mechanisms by which leucine stimulates insulin secretion is by allosterically activating glutamate dehydrogenase [1], [2], [3], [4], [5], [6], [7]. This enhances metabolism of glutamate which can act as a fuel to supply energy and metabolites for anaplerosis which is also believed to be important for insulin secretion [8]. The evidence for leucine stimulating insulin release via activation of glutamate dehydrogenase is quite strong and comes in part from studies with 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH), a non-metabolizable analog of leucine. Like leucine, BCH has been shown to both activate glutamate dehydrogenase and stimulate insulin release [1], [2], [3]. In addition, in in vitro experiments, when the insulin release incubation medium was supplemented with glutamine, which is a source of glutamate (By itself glutamine cannot stimulate insulin release [4], [5].), both leucine-induced and BCH-induced insulin releases were potentiated [1], [2], [3], [4], [5], [9]. Proof that activation of glutamate dehydrogenase can stimulate insulin secretion in vivo in humans is known from the hypoglycemic disorder that is characterized by dietary leucine sensitivity combined with increased blood insulin and ammonia. The disorder is associated with amino acid alterations in glutamate dehydrogenase in the region of the enzyme where GTP interacts and normally inhibits the enzyme. These mutations cause the enzyme to be constitutively active and the beta cell inappropriately metabolizing glutamate and secreting insulin and larger body tissues converting glutamate to ammonia [10].