Immunoliposome based targeting of RON receptor tyrosine kinase - A novel approach for epithelial cancer treatment

Aberrant expression of the RON receptor tyrosine kinase exists in numerous epithelial cancers, which provides a molecular basis for targeted cancer therapy. The current thesis focuses on the effectiveness of a novel RON targeted therapeutic approach for enhanced tumor cytotoxicity and investigation of underlying mechanism. Three projects were conducted. The first determines anti-RON antibody (Zt/g4 and Zt/c1) directed delivery of doxorubicin-immunoliposome (anti-RON-Dox-IL) to cancer cells overexpressing RON and their effectiveness in cytotoxicity. The second project studies dynamic RON expression under chronic hypoxia, which regulates cellular sensitivity towards targeted tyrosine kinase inhibitor. The third evaluates the cytotoxic efficiency of Zt/g4-RON-Dox-IL against acute hypoxic colon and breast cancer cells. Results from these studies demonstrate that RON overexpressed by normoxic tumor cells is a valid molecule for delivery of Zt/g4-Dox-IL with increased drug uptake and enhanced cytotoxicity. Interestingly, RON expression was progressively diminished under chronic hypoxia in various tumor cells, which is a novel mechanism for acquired resistance limiting the effectiveness of the targeted drug. However, by targeting acute hypoxic cancer cells with sustained RON expression, Zt/g4-directed Dox-IL delivery was able to achieve substantial cytotoxicity against tumor cells and to partially overcome the acquired resistance. We conclude from these studies that RON is a valid molecule for targeted drug delivery to increase chemotherapeutic cytotoxicity under normoxic conditions. Although chronic hypoxia impairs RON expression causing acquired resistance, Zt/g4-directed drug delivery has the ability to achieve enhanced cytotoxicity under acute hypoxia. Thus, anti-RON-immunoliposomes represent a novel therapeutic approach for potential cancer treatment in the future.