A molecular dissection of the interplay between diabetes and cancer: an integrated, multidisciplinary approach

This research combines molecular science, cell biology and disease processes - it is in molecular medicine. The research programme focuses on human insulin and Insulin-like Growth Factors I and II (IGF-I/II); these are closely related protein hormones. Their separate evolution has resulted in their acquiring separate biological functions, with insulin becoming a key regulator of metabolism, while IGF-I/II are major growth factors. When released into the blood the hormones bind, tightly and specifically, to their receptors, (Insulin Receptor (IR) and IGF-1R respectively); these are large complex protein molecules on the cell surface. Receptor binding, through which the hormone activity is expressed, involves structural changes in both the hormone and the receptors. Despite their fundamental medical importance (insulin: in diabetes, IGFs: in development, cancer, aging) the active conformations of the hormones in their hormone:receptor complexes are not known. Thus, more than 40 years after the first insulin crystal structure was determined, all the analogues used in treatment of diabetes are still based on the inactive/storage forms of this hormone. Insulin cross-reation with IGF-1R and its accumulation in Type 2 Diabetes entails this hormone in cell proliferation and growth. As IGF-I/II are also cancer-specific growth factors the identification of pure 'metabolic' and 'cell growth' structural signatures of insulin and IGF-I/II is of fundamental importance not only for the understanding of the biology of these hormones, but also for new, effective treatments of diabetes and cancer. Therefore this Programme is a response to an urgent need for a unique, consolidated, and multidisciplinary attack on these critical problems of insulin and IGF-I/II structure and biology. This programme combines fundamental (structural biology, cell signaling, organic and protein chemistry) and applied research. The fundamental research provides the foundations of the programme. However, advanced expertise of this group in the applied biomedical sciences will enable parallel pursuit of applied aims as well. This programme will deliver: (i) 3-D structural description of insulin:IR complexes; elucidation of the active form of human insulin, (ii) identification of active surfaces in insulin's responsible for metabolic effects, (iii) development of novel, specific metabolic insulin analogues, (iv) identification of the mitogenic structural signatures of the Insulin-like Growth Factors-I/II (IGF-I/II) expressed through IR, (vi) initiation of developing organo/peptido-mimetics of these hormones. We believe that the potential impacts on molecular cell biology and on medical science are immense as it addresses directly two major health problems, diabetes and cancer. Both have enormous social and economic consequences. (i) Firstly, solution of the central problem of diabetes: insulin-Insulin Receptor (IR) interaction, i.e. activation of insulin from its storage form to its IR stimulating conformation, will provide a long-awaited breakthrough in understanding of insulin structure-function relationships and open new possibilities for rational design of novel insulins. (ii) Subsequently, identification of structural determinants of insulin and IGF-I/II that govern their specific signaling pathways and which are responsible for metabolic and growth specificity of these hormones should enhance the prospects for rational design and production of pure and safe insulins without their undesired mitogenic properties. This is a problem indicated by some currently used clinical analogues. (iii) The studies should allow initiation of rational design and synthesis of IGF-I/II-specific antagonists for novel anti-cancer therapies. (iv) The firm control on hormone chemistry within this programme will also allow initiation of rational design and synthesis of organo-mimics of insulin, which may lead to insulin-like drugs suitable for oral delivery.