Targeting metabolism in pancreatic cancer

Abstract

Targeting altered metabolism in cancer is an intriguing concept. The Warburg effect—the observation that cancer cells use energy from glucose even when there is enough oxygen (aerobic glycolysis)—has been almost forgotten for a long time. However, recently, studies on cancer cell-specific metabolism have uncovered many of the biochemical mechanisms underlying this shift in energy provision. 1 Perera RM Bardeesy N Pancreatic cancer metabolism: breaking it down to build it back up. Cancer Discov. 2015; 5: 1247-1261 Crossref PubMed Scopus (125) Google Scholar Several drugs have been developed that target altered metabolic pathways in cancer. 2 Weinberg SE Chandel NS Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol. 2015; 11: 9-15 Crossref PubMed Scopus (932) Google Scholar Among these, CPI-613—an agent that inhibits cancer-specific mitochondrial energy metabolism—has recently gained attention and has been shown to be well tolerated and effective in various cancers. 3 Pardee TS Lee K Luddy J et al. A phase I study of the first-in-class antimitochondrial metabolism agent, CPI-613, in patients with advanced hematologic malignancies. Clin Cancer Res. 2014; 20: 5255-5264 Crossref PubMed Scopus (71) Google Scholar , 4 Lycan TW Pardee TS Petty WJ et al. A phase II clinical trial of CPI-613 in patients with relapsed or refractory small cell lung carcinoma. PLoS One. 2016; 11: e0164244 Crossref PubMed Scopus (41) Google Scholar In The Lancet Oncology, Angela Alistar and colleagues report the findings of their a phase 1 study to establish a maximum tolerated dose of CPI-613 in patients with metastatic pancreatic cancer. 5 Alistar A Morris BB Desnoyer R et al. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2017; (published online May 8.)http://dx.doi.org/10.1016/S1470-2045(17)30314-5 Summary Full Text Full Text PDF PubMed Scopus (139) Google Scholar The researchers not only postulated that CPI-613 would have few adverse events and that targeting tumour cell mitochondrial metabolism would exert anti-tumour effects, but that there would be synergy of CPI-613 with modified FOLFIRINOX chemotherapy. 5 Alistar A Morris BB Desnoyer R et al. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2017; (published online May 8.)http://dx.doi.org/10.1016/S1470-2045(17)30314-5 Summary Full Text Full Text PDF PubMed Scopus (139) Google Scholar Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trialA maximum tolerated dose of CPI-613 was established at 500 mg/m2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Full-Text PDF