Targeted Therapy of Fn14-Positive Breast Tumors Using a TWEAK-Cytotoxin Fusion Protein or Noncovalent Complex

摘要

Our laboratory research is focused on the potential roles of a TNF- related cytokine named TWEAK and its specific cell surface receptor named Fn14 in tumor biology. We reported previously that the Fn14 gene is highly expressed in many human breast cancers. In this Breast Cancer Concept Award application we proposed to investigate whether we could make Fn14-targeted toxins that would kill Fn14-positive breast cancer cells in vitro and in vivo. Our most significant findings during the research period are that although TWEAK-based single chain or two chain non-covalently linked toxins do have some cytotoxicity on cancer cells this approach is not ideal because of protein aggregation issues, likely problems with translating these molecules to clinical use, and the recent identification of a second TWEAK-binding protein. A different approach, namely using an Fn14 mAb named ITEM4 to deliver toxic cargo, appears to be a better strategy. Indeed, we have shown that both ITEM4- gelonin chemical conjugates and ITEM4/gelonin-based single chain proteins have cytotoxic activity on Fn14-positive breast cancer cells.