Despite refinements in surgery, radiation and chemotherapy, tlie mortality rates of women with advanced uterine carcinoma have remained largely unchanged for decades. Recognition of this """"""""therapeutic plateau"""""""" has focused intense investigation into strategies targeting mechanisms of tumor growth and progression. Our preliminary studies have identified a novel therapeutic target, EphA2, which is overexpressed in a substantial proportion of uterine cancers, is associated with poor overall survival, and mechanistically regulates angiogenesis. While present in tumor and tumor-associated vasculature, it is low or absent in most normal tissues, making its differential presence and function an attractive therapeutic target. The overall goal of this proposal is to develop EphA2 targeted therapeutic strategies for uterine carcinoma and to characterize its biological functions in regulating uterine cancer growth and progression. We will first leverage the differential expression of EphA2 in tissue as a targeting beacon to deliver a novel molecular immunoconjugate, monomethylauristatin F (MMAF;MEDI-547). This dolastatin-analogue is attached to a monoclonal antibody, which selectively binds EphA2. Our preliminary data demonstrate that MEDI-547 inhibits tumor growth and metastasis in orthotopic animal models of uterine cancer. However, it is not known whether EphA2 expression on the tumor cells is required for MEDI-547 to be efficacious. This question will be addressed experimentally in Aim 1. The findings from Aim 1 will guide a Phase Ib clinical trial in Aim 2 that will examine the safety, toxicity, and efficacy of the MEDI-547 in patients with recurrent uterine carcinoma. In addition to targeting EphA2 for delivery of a cytotoxic agent, our preliminary data suggest that EphA2 silencing can directly affect tumor and endotiielial cell functions. These effects may be mediated via reduced activation of downstream non-receptor kinases such as focal adhesion kinase (FAK). However, the mechanisms by which EphA2 regulates tumor growth are not fully understood and will be further examined in Aim 3. In this Aim, we will also examine the therapeutic efficacy of EphA2 gene silencing. To achieve efficient systemic in vivo delivery of short interfering RNA (siRNA) for gene silencing, we have developed and characterized biocompatible nanoparticle-based delivery methods that will be utilized for the experiments proposed in Aim 3.
There are not many options for treating advanced/recurrent endometrial cancer. Targeted therapy using monoclonal antibodies against tumor-specific antigens is a highly attractive therapeutic approach. EphA2 as a target for such therapy has theoretical advantages since it is overexpressed in a substantial proportion of tumors and is largely absent in most normal adult tissues. Moreover, EphA2 has been implicated in a number of processes related to cancer invasion, angiogenesis, and metastasis.
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