Overcoming physical barriers in cancer therapy

Abstract

Most solid tumors are of epithelial origin and, although malignant cells are de-differentiated, they maintain intercellular junctions, a key feature of epithelial cells, both in the primary tumor as well as in metastatic lesions. These intercellular junctions represent a protective mechanism against attacks by the host's immune system and pose as physical barriers that prevent intratumoral penetration and dissemination of cancer therapeutics. A key protein of epithelial junctions is desmoglein 2 (DSG2). DSG2 is consistently upregulated in all cancers analyzed. Recently, we demonstrated that a group of human adenoviruses (Ad serotypes 3, 7, 11 and 14) use DSG2 as a primary attachment receptor for the infection of cells. We subsequently created a small recombinant protein derived from Ad serotype 3, which binds to DSG2 and triggers transient opening of epithelial intercellular junctions. We named the protein "JO-1" ("junction opener -1"). JO-1 is a small protein that can easily be produced in E. coli. JO-1 binding to and clustering of DSG2 triggers an epithelial-to-mesenchymal-transition that results in transient opening of epithelial junctions. We have shown in over 25 xenograft tumor models that the intravenous injection of JO-1 increased the efficacy of monoclonal and chemotherapy, subsequently reducing the required treatment dose and concomitantly reducing the toxic side effect of these treatments. The application of JO-1 has not been associated with toxicities in safety studies performed in human DSG2-transgenic mice and monkeys.