Photochemical activation of MH3-B1/rGel: a HER2-targeted treatment approach for ovarian cancer

// Bente Bull-Hansen 1 , Maria B. Berstad 1 , Kristian Berg 1 , Yu Cao 2,5 , Ellen Skarpen 3 , Ane Sofie Fremstedal 1 , Michael G. Rosenblum 2 , Qian Peng 4 and Anette Weyergang 1 1 Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 2 Immunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX, USA 3 Department of Biochemistry, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 4 Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 5 Current address: The Scripps Research Institute, Department of Chemistry, La Jolla, CA, USA Correspondence to: Anette Weyergang, email: // Keywords : ovarian cancer, HER2/neu/ErbB2, immunotoxin, photochemical internalization, photodynamic Received : October 13, 2014 Accepted : March 11, 2015 Published : April 14, 2015 Abstract HER2-targeted therapy has been shown to have limited efficacy in ovarian cancer despite frequent overexpression of this receptor. Photochemical internalization (PCI) is a modality for cytosolic drug delivery, currently undergoing clinical evaluation. In the present project we studied the application of PCI in combination with the HER2-targeted recombinant fusion toxin, MH3-B1/rGel, for the treatment of ovarian cancer. The SKOV-3 cell line, resistant to trastuzumab- and MH3-B1/rGel- monotherapy, was shown to respond strongly to PCI of MH3-B1/rGel to a similar extent as observed for the treatment-sensitive SK-BR-3 breast cancer cells. Extensive hydrolytic degradation of MH3-B1/rGel in acidic endocytic vesicles was indicated as the mechanism of MH3-B1/rGel resistance in SKOV-3 cells. This was shown by the positive Pearson’s correlation coefficient between Alexa488-labeled MH3-B1/rGel and Lysotracker in SKOV-3 cells in contrast to the negative Pearson’s correlation coefficient in SK-BR-3 cells. The application of PCI to induce the release of MH3-B1/rGel was also demonstrated to be effective on SKOV-3 xenografts. Application of PCI with MH3-B1/rGel was further found highly effective in the HER2 expressing HOC-7 and NuTu-19 ovarian cancer cell lines. The presented results warrant future development of PCI in combination with MH3-B1/rGel as a novel therapeutic approach in preclinical models of ovarian cancer.

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