The AKT/mTOR/p70S6K1 pathway is hyperactive in a majority of ovarian tumours (Altomare et al. 2004). The pathway is associated with increased protein translation, enhanced angiogenesis, cell cycle regulation and proliferation. Rapamycine derivates can block this pathway by blocking the mTOR-raptor complex. Blocking the mTOR-raptor complex has already been conducted in phase II trials in refractory renal cell carcinoma, glioblastoma and breast cancer patients. The object of this project at the TCRG-Antwerp laboratory is to study this pathway in human epithelial ovarian cancer. This study will provide pre-clinical data whether it is feasible to inhibit mTOR in a clinical trial. Ovarian cancer is the most leading cause of death in gynecological malignancies. The incidence of ovarian carcinoma is about 1.5-2% in Western countries. Three quarters of these patients present with advanced disease (FIGO stage IIc-IV) which has predominantly spread in the peritoneal cavity. Because most patients presenting with metastatic ovarian cancer are not curable by surgery alone, chemotherapy represents an essential component of their treatment. With the best available combination (neo) adjuvant chemotherapy (the platinum-containing drugs cisplatin and carboplatin either used alone or in combination with the taxane paclitaxel) major responses are seen in up to 80-90% of the patients, and a complete remission can be obtained in up to 70% of these women. However more then 80% of patients with advanced ovarian carcinoma will develop recurrent disease after a median time interval of about 3 years and eventually die of the disease. There is an urgent unmet clinical need for new drugs capable of prolonging survival either by increasing long-term remission rates and/or duration as first-line treatment or to improve on outcomes of second-line therapy (Kelland et al 2005).
The AKT/mTOR/p70S6K1 pathway is hyperactive in a majority of ovarian tumours (Altomare et al. 2004). The pathway is associated with increased protein translation, enhanced angiogenesis, cell cycle regulation and proliferation. The object of this project at the TCRG-Antwerp laboratory is to study this pathway in human epithelial ovarian cancer. This study will provide pre-clinical data whether it is feasible to inhibit mTOR in a clinical trial.
