Phosphoinositide 3-Kinase Research in the LICR:
The Base of the PIRAMED

The phosphoinositide 3-kinase (PI3K) enzymes generate lipid second messengers that activate signal transduction proteins, such as Akt/PKB, which are crucial for growth, differentiation, survival, proliferation, and migration. The PI3Ks are thought to be involved in carcinogenesis through their central role in these cell processes, which go awry in cancer, and also because the principal PI3K antagonist, PTEN, is inactivated in many cancers 1.

The PI3K family is comprised of three classes of enzyme, with the Class I enzymes further classified into two groups. The Class IA PI3Ks are heterodimers comprised of one catalytic subunit (p110α, p110β, or p110δ) and one regulatory subunit (p85α, p85β, or p55γ), whilst the sole Class IB PI3K is comprised of the p110g catalytic subunit and the p101 regulatory subunit. Class IA PI3Ks are activated by tyrosine kinases and Ras, whilst the Class IB PI3K is activated by G-protein-coupled receptors and Ras. Class II PI3Ks (C2α, C2β, and C2γ) are thought to be activated by tyrosine kinases, whilst the Class III PI3K (Vps34) is thought to have a low constitutive activation 2. The redundancy between the PI3K isotypes, the precise activity of each enzyme, and even the specific in vivo products of each PI3K enzyme have remained largely unknown due to the difficulty in discriminating between the activity of each specific PI3K enzyme. The two known PI3K inhibitors, wortmannin and LY294002, are more general inhibitors for all PI3Ks, and do not distinguish between isotypes.

Much of the current knowledge of PI3Ks has been determined by the team led by Dr. Mike Waterfield, LICR Member, and Director of the London University College (UCL) Branch. Dr. Waterfield’s group has identified nearly all of the PI3K enzymes, and has extensively studied PI3K signal transduction and its role in cancer. Other teams of LICR scientists have been building on Dr. Waterfield’s work, including those led by: Dr. Carl-Henrik Heldin (LICR Member, and Director of the Uppsala Branch) and Dr. Rainer Heuchel (LICR Assistant Member, Uppsala Branch) who have investigated PI3K signaling in the course of their studies on platelet-derived growth factor (PDGF) signaling 3,4; Dr. Anne Ridley (LICR Member, UCL Branch), who has investigated the role of PI3K in cell migration and phagocytosis by macrophages 5,6; and Dr. Marketa Zvelebil (LICR Senior Investigator, UCL Branch) who has used protein modeling techniques to relate the function of PI3K enzymes to their structures (7). Recently, the team led by Dr. Bart Vanhaesebroeck (LICR Assistant Member, UCL Branch) generated transgenic mice with isotype-specific knockout and kinase-dead PI3Ks, and found that the Class IA PI3Ks play a vital role in lymphocyte development, differentiation and activation 8, with p110δ kinase-dead mice having impaired B and T cell antigen receptor signaling 9.

Given the central role of PI3K in the signal transduction of many carcinogenic processes, the potential for PI3K inhibitors as a cancer therapy has been obvious for some time. In 1997, Dr. Waterfield, Dr. Peter Parker from Cancer Research UK (CR UK, and formerly the Imperial Cancer Research Fund, ICRF), and Dr. Paul Workman from Institute for Cancer Research (London, UK) began ‘Project P’, a collaboration with the Japanese pharmaceutical company Yamanouchi Pharmaceutical Company Limited (Japan), to synthesize isotype-specific small molecule inhibitors of the PI3K family members. Several inhibitors were synthesized, and initial testing of the compounds showed them to be highly isotype-specific in vitro. However in 2002, Yamanouchi decided that their corporate interests lay largely in other areas of drug development. The compounds were destined to remain ‘on the shelf’, at a crucial stage in development, unless the facilities and funding for their continued development could be obtained. Thus the concept of forming PIRAMED was born.

The launch of PIRAMED Limited, a start-up company based on this inhibitor development, was announced in London on July 9th 2003 with the investment of £8 million (US $13.2 million) from JPMorgan Partners (the equity arm of J.P. Morgan Chase & Company) and Merlin Biosciences. The Board of Directors of PIRAMED is comprised of the foundation scientists (Drs. Waterfield, Parker and Workman), Dr. Akkaraju and Mr. Philip Rattle (Partners of JP Morgan Partners), and Dr. Sue Foden (Director of Merlin Biosciences). Dr. Akkaraju at JPMorgan Partners, said: “PIRAMED represents a truly unique opportunity to build a Company around world class scientists who have already made significant progress in developing potential and selective inhibitors to one of the most interesting targets in oncology today.”

PIRAMED Limited has licensed, from a research collaboration comprised of the LICR, Cancer Research UK (CR UK), the Institute of Cancer Research (ICR) in London, and the Yamanouchi Pharmaceutical Company Limited of Japan (Yamanouchi), the exclusive worldwide rights to patents covering small molecule inhibitors of the phosphoinositide 3-kinase (PI3K) enzyme family, and the technology for screening such compounds against one member of the family (PI3K p110α). It is important to note that the team at the LICR Office of Intellectual Property in London, and in particular Dr. Deborah Carter, has worked hard to ensure that the licenses held by PIRAMED Limited will not restrict, in any way, the LICR’s continuing research interests in PI3K signaling.

References

1. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, and Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu.Rev.Cell Dev.Biol. (2001) 17:615-675.

2. Vanhaesebroeck B and Waterfield MD. Signaling by distinct classes of phosphoinositide 3-kinases. Exp.Cell Res (1999) 253(1):239-254.

3. Heuchel R, Berg A, Tallquist M, Ahlen K, Reed RK, Rubin K, Claesson-Welsh L, Heldin CH, and Soriano P. Platelet-derived growth factor beta receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3' kinase signaling. Proc.Natl.Acad.Sci.U.S.A (1999) 96(20):11410-11415.

4. Hooshmand-Rad R, Hajkova L, Klint P, Karlsson R, Vanhaesebroeck B, Claesson-Welsh L, and Heldin CH. The PI 3-kinase isoforms p110(alpha) and p110(beta) have differential roles in. J.Cell Sci. (2000) 113 Pt 2:207-214.

5. Vanhaesebroeck B, Jones GE, Allen WE, Zicha D, Hooshmand-Rad R, Sawyer C, Wells C, Waterfield MD, and Ridley AJ. Distinct PI(3)Ks mediate mitogenic signalling and cell migration in macrophages. Nat.Cell Biol. (1999) 1(1):69-71.

6. Leverrier Y, Okkenhaug K, Sawyer C, Bilancio A, Vanhaesebroeck B, and Ridley AJ. Class I PI3K p110beta is required for apoptotic cell and Fcgamma R-mediated phagocytosis by macrophages. J Biol.Chem. (2003).

7. Zvelebil MJ, MacDougall L, Leevers S, Volinia S, Vanhaesebroeck B, Gout I, Panayotou G, Domin J, Stein R, Pages F, and Waterfield MD. Structural and functional diversity of phosphoinositide 3-kinases. Philos.Trans.R.Soc.Lond B Biol.Sci. (1996) 351(1336):217-223.

8. Okkenhaug K and Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat.Rev.Immunol. (2003) 3(4):317-330.

9. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, and Vanhaesebroeck B. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science (2002) 297(5583):1031-1034.

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