Common therapeutic target for both cancer and obesity

Abstract

Obesity and cancer are two interrelated conditions of high epidemiological need, with studies showing that obesity is responsible for nearly 25% of the relative contribution to cancer incidence. Given the connection between these conditions, a drug that can operate on both obesity and cancer is highly desirable. Such a drug is accomplishable through the development of potent anti-angiogenesis agents due to the shared underlying role of angiogenesis in the development of both diseases. Prior research has demonstrated a key role of type-2 methionine aminopeptidase (MetAP2) for angiogenesis, which has led to the development of numerous of novel inhibitors. Several irreversible MetAP2 inhibitors have entered clinical trials without great success. Though this lack of success could be attributed to off-target adverse effects, the underlying causes remain unclear. More promising reversible inhibitors have been recently developed with excellent pre-clinical results. However, due to insufficient knowledge of the biological functions of N-terminal protein processing, it is hard to predict whether these novel inhibitors would successfully pass clinical trials and thereby benefit cancer and obesity patients. Significantly more efforts are needed to advance our understanding of the regulation of methionine aminopeptidases and the processes by which they govern the function of proteins.

MetAP2 inhibition reduces food intake and body weight in a ciliopathy mouse model of obesity

“…Our study indicates that there are plausible targets of MetAP2 inhibition that effectively reduce hyperphagia and body weight and substantially improve metabolic parameters in a ciliopathy model. This substantiates the need for greater understanding of the biology of MetAP2 34 . Currently, agonists of the melanocortin 4 receptor, which is activated by the processed protein products of Pomc, are being tested in clinical trial to target obesity in patients with BBS and Alström Syndrome 35 .…”

Targeting methionine aminopeptidase 2 in cancer, obesity, and autoimmunity

“…Compound 17 reportedly led to sustained weight loss in obese rodents as well as to increased energy expenditure in human adipocytes derived from obese individuals [55]. Induced weight loss was caused by direct action of 17 on brown adipocytes [17] in contrast to previous hypotheses positing that weight loss activity was an indirect antiangiogenesis effect in adipose tissue [56].…”

“…Vasculature-related adverse events halted the development of Beloranib first and then ZFN-1061, the two lead candidates of Zafgen [52,53]. While weight loss activity of MetAP2i was initially thought to be related to angiogenesis inhibition on adipose tissue [56,68], later evidence suggests otherwise, with A-357300, Beloranib, and 17 shown to directly impact the metabolic signature of human primary adipocytes from obese individuals as well as brown adipocytes [17,55].…”

“…MetAP2 has attracted significant interest as a drug target in different diseases by major pharmaceutical companies over the years. Interestingly, nearly all MetAP2i that have reached clinical trials have been irreversible, fumagillin-like covalent MetAP2i, despite their evident liabilities [15,56]. These MetAP2i have subnanomolar potencies in endothelial cells and had promising results in preclinical models of cancer and obesity.…”

“…Are the differential systemic effects driven by distinct tissue distribution of each compound? Whether weight loss is due to the antiangiogenic activity of MetAP2 on adipose tissues [56,68] or a direct effect on adipocytes themselves [17] is still unclear, and some studies indicate independent mechanisms for each effect [48,50,51]. It will be necessary to understand the link between these different activities, however, to develop pharmacological compounds with a specific effect, which is important since a desired effect in a specific indication (e.g., weight loss in obese patients) might become an adverse event in another (e.g., weight loss in patients with advanced solid malignancies).…”