Identification of the molecular mechanism that leads to a resistance against pseudomonas exotoxin A based immunotoxins

• Applicant: Dr. Fabian Müller
• Subject Area: Hematology, Oncology
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 234512553

During the last decades, a vast variety of different immunotoxins were developed by fusing bacterial toxin components like the catalytic domain of pseudomonas exotoxin A (PE) to antibodies or receptor-binding ligands. A broadly evaluated representative of such targeted therapeutics is the fusion protein HA22 which is a combination of a CD22-binding FAB and PE which is effective in many B-cell lymphomas by ADP-ribosylation of the elongation factor 2 (EF2) and subsequently by inhibition of protein biosynthesis. Due to this event, the cell is driven into programmed cell death. Some lymphoma cells are resistant to the immunotoxin a priori. The group of Ira Pastan discovered HA22-resistant cells in which the EF2 gets ADP-ribosylated and protein synthesis stops, but the cells do not undergo apoptosis. Some of these primary HA22-resistant cells can be sensitized to HA22 by specific small molecule compounds. In the project proposed here, we will compare the protein expression profile of primary resistant, secondarily sensitized and primary sensitive cells with each other to elucidate the underling molecular mechanism behind this resistance. This knowledge will be used to predict response to therapy and thus save patients from ineffective treatment and, in addition, to boost the effects of ADP-ribosylating toxins.Since the broadly used ADP-ribosylating immunotoxins diphtheria toxin, cholix toxin, ricin, and pseudomonas exotoxin share a common apoptosis-inducing mechanism, this work is of great interest for numerous targeted therapies in modern oncology.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Ira Pastan, Ph.D.