Advancing Translational Understanding for Cancer and Obesity Therapy

I am excited by the publication of the first papers in ACS Pharmacology and Translational Science. In distinct ways, each provides an important example of how the application of interdisciplinary research can advance understanding of complex biological systems to provide a translational path for future therapeutic intervention.

The first study by Dr. Sunghoon Kim and colleagues (Kwon et al., 2018)¹ identifies an important functional connection between enzymes involved in translation and cell cycle control, with implications for specific subtypes of cancer. Cell cycle control is fundamental to normal development and physiology, and dysregulation of the cell cycle is a key feature of many cancers. Among the cyclins and cyclin-dependent kinases (CDKs), abnormal increases in the level of CDK4 is a common feature of many cancers, and has been linked to tumor progression. The work of Kwon et al.,¹ identifies an unexpected functional role for methionyl-tRNA synthetase (MRS) in the maintenance of cell cycle progression by stabilizing formation of complexes between CDK4 and chaperone proteins. MRS competes with the binding of the tumor suppressor gene p16^INK4a, an endogenous CDK4 inhibitor, and was shown to be upregulated in multiple cancers, with a high correlation between MRS and CDK4 levels in p16^INK4a-negative cancer cells. Both chemical inhibition and knockdown of MRS inhibited p16^INK4a-negative cancer cell proliferation and MRS knockdown could inhibit tumor growth in in vivo xenograft experiments. Thus, the work of Kwon et al.,¹ expands our understanding of the biology of cell cycle control and identifies a novel mechanism for potential cancer intervention.

The second study, by Dr. Debbie Hay and colleagues (Bower et al., 2018),² is focused on peptide hormone therapies for diabetes and obesity. Obesity is epidemic, a massive health problem in westernized societies and an emerging problem in other cultures. There are very few approved medicines, and the high degree of redundancy in metabolic control mechanisms limits the potential for monotherapies. The pancreatic hormone, amylin, plays a physiological role in appetite control and preclinical assessments have demonstrated synergy in the combined use of amylin mimetics with other peptide hormones for weight control.^3,4 While the amylin analogue, pramlintide, is approved for treatment of type I diabetes, the potential for improved amylin peptides has not been effectively explored. In part, this may be due to the complexity of amylin receptors that are heteromers of the CALCR G protein-coupled receptor, and one of three receptor activity-modifying proteins (RAMPS). This is addressed in the work of Bower et al.,², who provide a comprehensive analysis of the 37-amino acid amylin peptide sequence linked to multiple functional end points across distinct amylin receptor subtypes. The work provides an important template for development of novel peptide therapeutics, illustrated by a dual amylin-GLP-1 peptide agonist with preserved activity at each of the target receptors.

Both these papers exemplify the application of detailed interdisciplinary research to advance concepts with current or future translational ramifications, and reflect different types of innovative research that sit within the scope of ACS Pharmacology and Translational Science.

Views expressed in this editorial are those of the author and not necessarily the views of the ACS.