A study published by Nature has defined the function of p110 alpha, the flag-ship molecule of the eight member PI3K family, which is one of the most frequently activated pathways in cancer. The function of p110 alpha in the body has eluded researchers for over a decade but a new approach to generating mouse models, has allowed investigators from the Ludwig Institute for Cancer Research’s (LICR) UCL Branch and the UCL Centre for Diabetes & Endocrinology to solve the mystery and yield important information for planned clinical trials with PI3K inhibitors.
The study showed that p110 alpha controls the action of insulin and other key hormonal signals that play roles in growth, diabetes and obesity. p110 alpha is frequently mutated or overexpressed in cancer, and the results of the present work imply that cancer cells hijack a key signalling pathway to fuel their energy needs and drive their proliferation and survival. The current work has far-reaching implications, given that several million of people are affected by metabolic disorders, and every year, several hundreds of thousand new cancer cases with mutations in p110 alpha are diagnosed.
Importantly, says LICR’s Dr. Bart Vanhaesebroeck, the senior author of the study, the findings have immediate implications for the testing of p110 alpha-specific inhibitors for human therapies. “Accurate information on the specific role of p110 alpha is needed urgently by the pharmaceutical industry, which is preparing to initiate clinical trials based on PI3K inhibition, not only in cancer but also in inflammation, allergy and auto-immunity. These mice mimic the effect of systemic administration with a p110 alpha-specific drug,”
According to Dr. Vanhaesebroeck, traditional mouse models investigating the function of PI3K proteins have been engineered to completely remove the p110 alpha gene. However the LICR and University College London team and collaborators from the Universities of Edinburgh and Fribourg introduced a single mutation into the p110 alpha gene that inactivates, but does not remove, the protein. The scientists discovered that the mice were smaller, but ate more and had increased levels of body fat. Additionally, the mice had raised insulin levels and were glucose-intolerant. However, the mice did not go on to develop full diabetes. “The finding that these mice, despite having dampened insulin signalling, showed no signs of developing diabetes, is welcome news, as this suggest that drugs that block p110 alpha function in cancer cells may not have the severe metabolic disturbances first expected.”
For Dr. Dominic Withers from the UCL Centre for Diabetes & Endocrinology, a senior co-author on the study, this work adds another important part to solving the puzzle of how insulin works. “In order to be able to treat diabetes and other metabolic disorders, such as obesity, we first have to understand the normal regulation of this complex system, so that therapies are targeted at the key players in this pathway.”
This study was conducted by investigators from the: University College London Branch of the Ludwig Institute for Cancer Research (UK); Centre for Diabetes & Endocrinology, Rayne Institute, University College London (UK); The Institute for Stem Cell Research, University of Edinburgh (UK); Department of Medicine, University of Fribourg (Switzerland). This study was funded in part by a grant from Diabetes UK.
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