Modulators of Response to Tumor Necrosis-Related Apoptosis-Inducing Ligand (TRAIL) Therapy in Ovarian Cancer; Annual rept. 1 Apr 2007-31 Mar 2008

摘要

Ovarian cancer is the leading cause of death from gynecologic cancers in the developed world. Most ovarian cancers are diagnosed late and current treatment results only in a 20% 5-year survival in advanced disease. More effective therapies are urgently needed. One of the most promising therapies in development for ovarian cancer is the use of either the Tumor Necrosis Factor-related Apoptosis Inducing Ligand (TRAIL) or agonistic antibodies that activate the receptors for TRAIL. Both these strategies are designed to induce apoptosis in ovarian cancer cells. TRAIL therapies are particularly exciting because TRAIL reverses chemoresistance to standard chemotherapy as well as having a direct growth inhibitory effect on ovarian cancer cells, while sparing normal ovarian cells. However, the characteristics of ovarian tumor cells that determine whether TRAIL pathway agonists will be effective are poorly understood. For this reason, we currently do not have a rational basis for selecting patients who will benefit most from drugs that target this pathway or for improving the clinical response in those patients whose tumors are refractory to TRAIL pathway activators. We have identified a homeobox gene, Six1, which is over-expressed in ovarian cancers as compared to normal ovarian surface epithelium. Expression of Six1 is correlated with poor clinical prognosis and confers resistance to TRAIL, possibly via upregulation of a decoy receptor. If this is the case, tumor cells would be expected to be resistant to TRAIL, but not to TRAIL agonistic antibodies. We hypothesize that Six1 expression in ovarian cell lines and primary tumor cells results in resistance to TRAIL-induced apoptosis through activation of the DcR1 decoy receptor.