Novel biologic therapies for the treatment of endometrial cancer

Abstract

Over the past 20 years, options for patients with recurrent endometrial cancer have included radiation, chemotherapy, and hormonal therapy. None of these options have been shown to greatly impact mortality. We are currently investigating the role of molecular therapeutics for the treatment of this disease. By better understanding molecular pathways that are disregulated, we hope to identify rational biologic targets. PTEN, a tumor suppressor gene, has been shown to play several roles in tumor suppression, including cell cycle arrest and promotion of apoptosis. The finding of PTEN mutations in 40–50% of endometrial cancers suggests this pathway is important in the pathogenesis of this disease. Loss of PTEN leads to constitutive activation of AKT, which in turn leads to upregulation of the mammalian target of rapamycin (mTOR). Because PTEN-deficient cancer cells may have upregulated activity of the mTOR, these cells may be sensitive to mTOR inhibition. Our preliminary findings have demonstrated phosphorylated mTOR expression in over 70% of preliminary endometrial cancers and over 50% of recurrent endometrial cancers. In addition, expression of mTOR is present in all endometrial cancer cell lines studies. RAD001 is a novel macrolide, which is being developed as an antiproliferative drug with applications as an immunosuppressor and anticancer agent. In a phase II study, we are currently evaluating RAD001 for the treatment of recurrent endometrioid endometrial cancer. The epidermal growth factor receptor (EGFR) is overexpressed in the two most common histologic subtypes of endometrial cancer: uterine papillary serous carcinoma (UPSC) and endometrioid endometrial cancer. Overexpression of this receptor has been associated with advanced stage disease and a poor prognosis. Because of this, we hypothesize that targeting this receptor may help stabilize disease in those patients with recurrent disease. We are in the process of initiating a phase II trial evaluating Erbitux (anti-EGFR antibody) for the treatment of recurrent endometrial cancer. Finally, we have previously reported that imatinib targeted kinases are overexpressed in endometrial carcinomas, specifically UPSC. In a phase I/II study, we are evaluating the combination of Gleevec and paclitaxel for the treatment of advanced and recurrent UPSC. We feel that these studies may provide important information that will help improve the survival in the patients with recurrent endometrial cancer. In addition to clinical endpoints, we will be evaluating specific biologic endpoints that may help us to pre-select patients for specific therapies and identify which agents may work in combination with other cytotoxic or biologic therapies.