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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

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The chemical signaling pathways that control the life cycle of cells offer many important targets for cancer researchers hoping to stop the growth of tumours, yet the complex nature of these pathways may make it virtually impossible to kill a cell with a single therapeutic bullet.

Mutations in genes that encode components of the phosphoinositide 3-kinase (PI3K) pathway are one of the most frequent events observed in solid tumours.  The PI3K pathway can be activated by overproduction of growth factors, chemokines or mutations in growth factor factor receptors such as Ras, PTEN or P3IK itself.  Activation of the PI3-kinase pathway has been linked to a diverse group of cellular functions, including cell growth, proliferation, differentiation, motility and survival, all important aspects of tumourigenesis.

Genetic studies in mice reveal that the insulin-like growth factor (IGF), PI3K and Akt pathway provides a synergistic signal for Hedgehog tumour formation. Interestingly, there is a high incidence of loss-of-function mutations of PTEN, a negative regulator of PI3-kinase activity, in approx. 39% of Hedgehog-dependent human pancreatic cancers. 
Researchers have looked at inhibition of PI3-kinase in a study of breast cancer cells.  Their findings suggest that molecules used to inhibit the MEK protein, similar to those being studied to control breast cancer growth, can "switch on" another pathway that keeps cancer cells from dying.

At the recent ASCO meeting in Chicago, a number of papers were presented looking at prognostic factors, proteomic analysis and various inhibitors in early phase clinical trials, including XL765 from Exelixis, temsirolimus from Wyeth, NVP-BEZ235 and SF1126.  It is too early to tell if the pathway is critical to the tumour's survival, but time will tell.

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