COMBINATION THERAPIES INCLUDING INHIBITORS OF THE EXTRACELLULAR DOMAIN OF E-CADHERIN

摘要

The present invention is based on our work with E-cadherin, including soluble portions of this integral membrane glycoprotein. The compositions of the present invention include therapeutically effective amounts of a first agent that targets epitopes within one or more of the EC2-EC5 subdomains of the ectodomain of E-cadherin (induing these domains in the shed sEcad fragment) and a second agent that inhibits one or more of: endothelial tube formation; angiogenesis; the human epidermal growth factor receptor family (i.e. HER1-4); an insulin-like growth factor 1 receptor (IGF-1R); any other receptor tyrosine kinase receptor family member; the P13K-MAPK pathway; and the P13K/Akt/mTOR pathway. The compositions can be used in the treatment of epithelial cancers, and may effectively inhibit cellular proliferation, migration, and/or invasiveness. Thus, the present compositions can be used to inhibit tumor growth and metastasis. The present compositions can be used in the treatment of "triple negative" breast cancer patients (in whom breast cancer cells test negative for estrogen receptors, progesterone receptors, and HER2), as well as HER2 -positive and other HER2 -negative tumors. In addition to therapeutic and prophylactic treatment methods, the invention features methods in which cancer is staged depending on the relative amounts of full-length (FL) E-cadherin and soluble E-cadherin (sEcad) and/or with another predictive biomarker for cancer. The greater the amount of sEcad relative to the amount of FL E-cadherin, the more advanced the cancer.