Investigational cancer drugs targeting cell metabolism in clinical development

Abstract

Introduction Malignant cell transformation and tumor progression are associated with alterations in glycolysis, fatty acid synthesis, amino acid delivery and production of reactive oxygen species. With increased understanding of the role of metabolism in tumors, there has been interest in developing agents that target tumor specific metabolic pathways. Numerous promising agents targeting altered metabolic pathways are currently in Phase I – III clinical trials. Areas covered This paper reviews the early phase clinical trial development of these agents and provides perspective on the future direction of this emerging field. Specifically, the authors describe novel and repurposed therapies, focusing on the effects of each agent on tumor metabolism and results from relevant Phase I and II clinical trials. Expert opinion Metabolism modulating agents, alone and in combinations with other classes of agents, have shown efficacy in the treatment of neoplasm, which, the authors believe, will bear positive results in future studies. Because of the significant crosstalk between metabolic pathways and oncogenic signaling pathways, the authors also believe that combining metabolic modifiers with targeted agents will be an important strategy. An increased understanding of cancer metabolism, in addition to the continued study of metabolic modulators, should lead to further advances in this nascent therapeutic field in the future.

Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy

“…One such HK inhibitors in the clinic is Lonidamine (TH-070), a derivative of indazole-3-carboxylic acid. A Phase II trial in 35 patients with ovarian cancer showed an 80% objective response rate (ORR) of TH-070 in combination with paclitaxel and cisplatin (35). A Phase II trial in 31 patients with NSCLC who were treated with TH-070 in combination with cisplatin, epidoxorubicin and vindesine showed 89% of patients had either a partial remission (PR) or stable disease (SD) (35).…”

“…A Phase II trial in 35 patients with ovarian cancer showed an 80% objective response rate (ORR) of TH-070 in combination with paclitaxel and cisplatin (35). A Phase II trial in 31 patients with NSCLC who were treated with TH-070 in combination with cisplatin, epidoxorubicin and vindesine showed 89% of patients had either a partial remission (PR) or stable disease (SD) (35). Despite this early promising trials, TH-070 development was terminated after disappointing results in two randomized Phase III trials (35).…”

“…However, dose escalation Phase I trials in patients with castrate-resistant prostate cancer and other advanced solid tumors resulted in asymptomatic QTc prolongation that limited further drug evaluation (35). …”

“…Clinical trials (Phase I) with DCA in glioma patients revealed manageable tolerability and hints of objective responses (38). Although a phase II trial of DCA in non-small cell lung cancer was stopped early due to treatment-related deaths and lack of clinical benefit (39), encouraging preclinical results were reported for the combination of DCA plus 5-FU and cisplatin in gastric cancer (35). DCA is being currently evaluated in patients with head and neck cancer, glioblastoma and other solid tumors.…”

“…This is an oncometabolite that deregulates chromatin remodeling enzymes, resulting in epigenetic silencing of tumor suppressor loci and differentiation block in AML (34). Early trials with mutant IDH1 (AG-120) and IDH2 (AG-221) inhibitors produced impressive objective responses in 60% of AML patients (including complete responses with or without platelet response) (35), opening new therapeutic prospects for high-risk (>60 years of age) AML patients. A second approach of mitochondrial therapeutics focused on agents that elevate toxic ROS levels from a leaky electron transport chain.…”