=20

Ludwig Institute for Cancer Research

News

April 12, 2006

Diabetes and Cancer: Alpha Connection

Protein frequently mutated in cancer has a = surprising=20 alter-ego

(London, April 12) =E2=80=94 A study published by Nature = today has defined=20 the function of p110 alpha, the flag-ship molecule of the eight member = PI3K=20 family, which is one of the most frequently activated pathways in = cancer. The=20 function of p110 alpha in the body has eluded researchers for over a = decade but=20 a new approach to generating mouse models, has allowed investigators = from the=20 Ludwig Institute for Cancer Research=E2=80=99s (LICR) UCL Branch and the = UCL Centre for=20 Diabetes & Endocrinology to solve the mystery and yield important=20 information for planned clinical trials with PI3K inhibitors.

The study showed that p110 alpha controls the action of insulin and = other key=20 hormonal signals that play roles in growth, diabetes and obesity. p110 = alpha is=20 frequently mutated or overexpressed in cancer, and the results of the = present=20 work imply that cancer cells hijack a key signalling pathway to fuel = their=20 energy needs and drive their proliferation and survival. The current = work has=20 far-reaching implications, given that several million of people are = affected by=20 metabolic disorders, and every year, several hundreds of thousand new = cancer=20 cases with mutations in p110 alpha are diagnosed.

Importantly, says LICR=E2=80=99s Dr. Bart Vanhaesebroeck, the senior = author of the=20 study, the findings have immediate implications for the testing of p110=20 alpha-specific inhibitors for human therapies. =E2=80=9CAccurate = information on the=20 specific role of p110 alpha is needed urgently by the pharmaceutical = industry,=20 which is preparing to initiate clinical trials based on PI3K inhibition, = not=20 only in cancer but also in inflammation, allergy and auto-immunity. = These mice=20 mimic the effect of systemic administration with a p110 alpha-specific=20 drug,=E2=80=9D

According to Dr. Vanhaesebroeck, traditional mouse models = investigating the=20 function of PI3K proteins have been engineered to completely remove the = p110=20 alpha gene. However the LICR and University College London team and=20 collaborators from the Universities of Edinburgh and Fribourg introduced = a=20 single mutation into the p110 alpha gene that inactivates, but does not = remove,=20 the protein. The scientists discovered that the mice were smaller, but = ate more=20 and had increased levels of body fat. Additionally, the mice had raised = insulin=20 levels and were glucose-intolerant. However, the mice did not go on to = develop=20 full diabetes. =E2=80=9CThe finding that these mice, despite having = dampened insulin=20 signalling, showed no signs of developing diabetes, is welcome news, as = this=20 suggest that drugs that block p110 alpha function in cancer cells may = not have=20 the severe metabolic disturbances first expected.=E2=80=9D

For Dr. Dominic Withers from the UCL Centre for Diabetes & = Endocrinology,=20 a senior co-author on the study, this work adds another important part = to=20 solving the puzzle of how insulin works. =E2=80=9CIn order to be able to = treat diabetes=20 and other metabolic disorders, such as obesity, we first have to = understand the=20 normal regulation of this complex system, so that therapies are targeted = at the=20 key players in this pathway.=E2=80=9D

=E2=80=93 END =E2=80=93

This study was conducted by investigators from the: University = College London=20 Branch of the Ludwig Institute for Cancer Research (UK); Centre for = Diabetes=20 & Endocrinology, Rayne Institute, University College London (UK); = The=20 Institute for Stem Cell Research, University of Edinburgh (UK); = Department of=20 Medicine, University of Fribourg (Switzerland). This study was funded in = part by=20 a grant from Diabetes UK.

For further details, please contact:

Ludwig Institute for Cancer Research

Dr. Bart Vanhaesebroeck, UCL Branch
bartvanh@ludwig.ucl.ac.uk+44=20 (0)77 666 00 923 (Business hours, London)

Dr. Sarah White, Director, Office of Communications
swhite@licr.org
+1 212 450 1543 = (Business=20 hours - New York)
+1 917 974 7952 (After hours - New York)

University College London (for information relating to diabetes and=20 obesity)

Dr. Dominic Withers
d.withers@ucl.ac.uk
+44 (0)20 = 7679 6586=20 (Business hours, London)
+44 (0)796 896 1438 (After hours, London) =

The Ludwig Institute for Cancer Research (LICR) is = the=20 largest international academic institute dedicated to understanding and=20 controlling cancer. With ten Branches in seven countries, and numerous=20 Affiliates and Clinical Trial Centers in many others, the scientific = network=20 that is LICR quite literally covers the globe. The uniqueness of LICR = lies not=20 only in its size and scale, but also in its philosophy and ability to = drive its=20 results from the laboratory into the clinic. LICR has developed an = impressive=20 portfolio of reagents, knowledge, expertise, and intellectual property, = and has=20 also assembled the personnel, facilities, and practices necessary to = patent,=20 clinically evaluate, license, and thus translate, the most promising = aspects of=20 its own laboratory research into cancer therapies.

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