Treatment and molecular characterization of patient-derived hepatocellular carcinoma xenografts

• Applicant: Dr. Mohammad Kabbani
• Subject Area: Gastroenterology ; Hematology, Oncology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 380032518

Locally advanced and metastatic hepatocellular carcinoma (HCC), which a majority of HCC patients presents, has a poor overall outcome. Only the multikinase inhibitor sorafenib was shown to result in a modest but significant overall survival benefit from 8 to 11 months as a first line therapy, proofing that a mostly chemotherapy and otherwise radiation resistant tumor can be treated with targeted therapy. Several randomized phase III clinical trials investigating other molecular therapies failed to show improvement in overall survival compared to sorafenib. Inner- and intertumor heterogeneity, genetic and molecular variations as well as missing of predictive treatment response biomarkers are one the major reasons why clinical studies with new therapeutic agents have failed to show improvement in overall survival. Recently, a major step forward was achieved with regorafenib in the second-line setting after failure with sorafenib, showing improvement in overall survival (10.6 vs 7.8 months; p < 0.001) and progression free survival (3.1 vs 1.5 months; p < 0.001) in a randomized phase III prospective clinical trial testing regorafenib vs. placebo. It is not clear yet how regorafenib could overcome sorafenib resistance, despite sharing similar mechanisms of action. On the other hand, mechanisms of resistance to regorafenib are largely unknown.Xenotransplantation of primary human tumors into mice, commonly called patient-derived xenografts (PDX), has proven useful to advance studies into basic biology and to test anti-tumor strategies for breast, colorectal and several other cancers. However, only a few PDX series have been reported for HCC. In this project, we will molecularly compare the PDX and patient HCC after sorafenib treatment and test in PDX mice if regorafenib response requires previous sorafenib exposure. In addition, we will compare the regorafenib response in patients and PDX mice derived from patients that failed under sorafenib. Furthermore, molecular and genomic analysis will be perfomed in PDX mice and patients to identify mechanisms leading to regorafenib resistance after failure with sorafenib in HCC.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Charles M. Rice, Ph.D.