Akt Inhibitors to Treat Ewing's Sarcoma


Principal Investigator: Jeffrey Toretsky
Abstract: Novel drugs that improve overall survival with decreased morbidity are critical in the war on cancer. Acenta Discovery Inc. has partnered with the Toretsky Lab of the Lombardi Cancer Center to create and preclinically evaluate novel inhibitors of the protein Akt. An Akt inhibitor would have tremendous value in improving the lives of patients with many types of cancer and lead to a successful commercial venture. Akt modulated survival signaling enables tumors to survive cytotoxic chemotherapy. Inhibition of Akt signaling will reduce tumor survival thereby enhancing the effectiveness of cytotoxic chemotherapy by increasing apoptosis. This augmentation of cytotoxicity could be the difference between disease-free survival and relapse following a state of minimal residual disease. Since the recruitment of Akt to the cell membrane with phosphatidylinositol is critical for Akt to function, analogues of phosphatidylinositol have been developed that block Akt movement to the membrane without affecting the function of other lipid dependent molecules. We have a model of Ewing's sarcoma family of tumors (ESFT) that demonstrates Akt as critical for sensitivity to chemotherapy. In addition, clinical survival rates for patients with ESFT are poor, especially for patients with metastatic disease. It is well established that patients with ESFT often respond well to initial chemotherapy, however, relapse occurs at metastatic sites indicating that a subpopulation of tumor cells survived the initial cycles of therapy. One mechanism that could explain tumor cells surviving chemotherapy is the ability for IG F-I to activate survival pathways through Akt and avoidance of cell death. ESFT are known to rely on signaling through the insulin-like growth factor type I receptor (IGF-IR) for their survival (via Akt) and growth (via MAP kinase). Our previous work implicates PI 3-K and Akt as important survival molecules in ESFT. ESFT cells growing in spheroid culture demonstrate constitutively activated Akt. We hypothesize that Akt is a therapeutic target in patients with ESFT and that the development of clinical molecules that specifically block Akt function will improve patient survival. This proposal~ will evaluate a series of molecules that specifically block Akt function and determine if these molecules function to enhance chemotherapy effects in xenograft models of ESFT. Our findings from this Phase I Sun will hopefully lead to a key compound that can be further developed in a Phase II STTR ultimately leading to clinical trials in patients with ESFT.
Funding Period: 2004-08-02 - 2007-07-31
more information: NIH RePORT