Understanding the mechanism of action of classic cytotoxic chemotherapeutic agents using intravital live-cell imaging in mice

• Applicant: Dr. Stefan Florian
• Subject Area: Cell Biology
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 221468111

Despite continuous effort to improve chemotherapy, cancer is still one of the main causes of mortality. During the last 3 decades, progress in the molecular understanding of tumor biology has enabled the design of new "targeted" chemotherapeutic drugs which exploit tumor-specific molecular defects. Nevertheless, to date, the most important drugs in chemotherapy are still emprically found traditional cytotoxic drugs which are thought to kill proliferating cells, no matter if malignant of not. This "antiproliferative" model is based on results from the 1970s coming from mouse leukemia models or cell culture experiments. However, new antiproliferative drugs designed from scratch have repeatedly failed in clinical trials, suggesting that the mechanism of action of these drugs is still not well understood. In this project, I will analyze the mechanism of action of cytotoxic drugs using live-cell imaging in mice. Intravital imaging will allow me to observe their effect on solid tumor xenografts directly. We will use genetically manipulated tumor cell lines which will allow us to determine the cell cycle state of the cells directly as well as drug resistant cell lines which should not be affected by direct effects of the drug. Thus, I will be able to test the antiproliferative model in solid tumors and try to understand if alternative factors like host immune mechanisms or specific genetic defects of the tumor are required for therapeutic success. Improved understanding of the effect of cytotoxic drugs in vivo will expand our knowledge about tumor biology and host-tumor interactions and hopefully pave the way to hypothesis driven rather than empirical development of new cytotoxic drugs.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Timothy Mitchison