LY317615 Enzastaurin any more combinations with rapalogs currently under evaluation

Amongst the PI3K pathway inhibitors, a host of phase I studies LY317615 Enzastaurin evaluating combination strategies are underway. As seen in table 3, co administration with either molecular targeted therapies, as well as cytotoxic agents, is being evaluated. Finally, there is some evidence showing that inhibition of the PI3K pathway can lead to hyperactivation of the MAPK pathway, and hence combinations of PI3K inhibitors and MEK inhibitors may be a promising therapeutic strategy. CONCLUSION The rapalogs provide one avenue for inhibiting the PI3K Akt mTOR pathway. They have had some success but left much room for improvement. As the newer agents progress through clinical evaluation inhibitors of PI3K, Akt, and mTOR kinase inhibitors the early findings suggest the drugs are relatively well tolerated and that pathway downregulation is being achieved.
However, there have been relatively few clinical responses, even amongst those patients with PTEN loss or activating mutations of PI3K. Irrespective, investigators are devising and employing new strategies to enhance outcomes, in particular by enriching patient populations and testing a multitude of drug combinations based on sound rationale. AS-605240 In addition, agents targeting other components of the pathway are under development. These include PDK1 inhibitors, SHIP agonists, and heat shock protein inhibitors. Given the importance of the PI3K pathway in the malignant phenotype, further optimization of the clinical use of these new compounds in the coming years is warranted and should lead to better patient outcomes.
Lung cancer is the leading cause of cancer related death worldwide. In the United States alone, about 222,520 new cases were diagnosed and about 157,300 deaths occurred due to lung cancer in 2010. Non small cell lung cancer represents about 80 of all lung cancer. The most common histologies are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. The majority of NSCLC patients are diagnosed at advanced stage where chemotherapy may improve survival and palliation of symptoms. However, conventional chemotherapy provides no cure for advanced NSCLC and has reached a plateau in efficacy with a median survival of 8 10 months. The addition of new targeted therapies such as bevacizumab and cetuximab to conventional chemotherapy has improved the median survival to about 12 months in patients with good performance status.
Novel therapeutic approaches are urgently needed for this common disease. The phosphatidylinositol 3 kinase AKT mTOR signaling pathway impacts many aspects of cell growth and survival. Alterations of components in the PI3K AKT mTOR pathway can occur at many levels and result in constitutive activation of this pathway and malignant transformation. The PI3Ks are a family of enzymes that phosphorylate phosphatidylinositol biphosphate to phosphatidylinositol triphosphate. PI3Ks are most often activated by receptor tyrosine kinase sig