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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Bottsford-Miller, Justin; Choi, Hyun-Jin; Dalton, Heather J et al. (2015) Differential platelet levels affect response to taxane-based therapy in ovarian cancer. Clin Cancer Res 21:602-10
Wen, Yunfei; Graybill, Whitney S; Previs, Rebecca A et al. (2015) Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer. Clin Cancer Res 21:448-59
Previs, Rebecca A; Coleman, Robert L; Harris, Adrian L et al. (2015) Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer. Clin Cancer Res 21:955-61
Yang, Lifeng; Moss, Tyler; Mangala, Lingegowda S et al. (2014) Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. Mol Syst Biol 10:728
Cho, Min Soon; Vasquez, Hernan G; Rupaimoole, Rajesha et al. (2014) Autocrine effects of tumor-derived complement. Cell Rep 6:1085-95
Yang, Yang; Han, Leng; Yuan, Yuan et al. (2014) Gene co-expression network analysis reveals common system-level properties of prognostic genes across cancer types. Nat Commun 5:3231
Wu, Sherry Y; Lopez-Berestein, Gabriel; Calin, George A et al. (2014) RNAi therapies: drugging the undruggable. Sci Transl Med 6:240ps7
Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202-9
Peng, Guang; Chun-Jen Lin, Curtis; Mo, Wei et al. (2014) Genome-wide transcriptome profiling of homologous recombination DNA repair. Nat Commun 5:3361
Liu, Guoyan; Sun, Yan; Ji, Ping et al. (2014) MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer. J Pathol 233:308-18

Showing the most recent 10 out of 148 publications