Molecular targeting: PI3 kinase pathway

Abstract

In summary, agents in clinical development that target the PI3K-Akt pathway are currently limited to the rapamycins, which inhibit the downstream kinase mTOR, and multi-targeted inhibitors UCN-01, perifosine and 17AAG. Whether modulating downstream targets such as mTOR rather than PI3K and Akt will provide a better therapeutic index or whether simultaneously modulating multiple signaling pathways will have greater therapeutic effect remain unanswered questions. Certainly, general principles can be applied to the eventual clinical development of agents that specifically inhibit PI3K and Akt. It would be preferable to have a robust method to identify PI3 kinase pathway activation and signaling that can be applied to pathological specimens to select the patient population to study these agents. Testing the effect of the agent on its target in patients is difficult but may be necessary to determine the appropriate dose if minimal toxicity is seen with these agents or to limit toxicity by selecting a biologically active dose based on target modulation that may be below the MTD. Clinical end points for assessing antitumor activity should be based on whether tumor regression or tumor stabilization is seen in pre-clinical models. Similarly, the schedule of administration of the single agent and of combinations with standard cytotoxics and other molecularly targeted agents should be driven by the results of pre-clinical studies. Given the frequent implication of the PI3K pathway in the pathophysiology of human malignancy, there is every reason to be optimistic that inhibition of the pathway will induce antitumor effects in cancer patients. Small molecules designed to specifically target components of the pathway are now being developed for clinical testing. As with other signal transduction inhibitors, the major clinical development challenges will be efficiently identifying the appropriate dose, schedule and combination regimens for patients with susceptible malignancies. © 2004 European Society for Medical Oncology.