Analyzes of the impact of GAS6/AXL signaling on hypoxia-induced metastasis and its therapeutic potential for the treatment of advanced hepatocellular carcinoma

• Applicant: Dr. Anne Ernst
• Subject Area: Gastroenterology ; Hematology, Oncology
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409925158

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is one of the most lethal cancers worldwide. Early diagnosis is rare, and advanced disease stages show a 5-year overall survival of less than 5% due to limited treatment options. HCC patients typically die due to their metastases. Hence, understanding the underlying mechanisms of tumor progression and metastasis are fundamental to identify new therapeutic targets to improve patient outcome. GAS6/AXL signaling has recently emerged as a compelling therapeutic target for multiple cancers. In HCC, the overexpression of AXL, a receptor tyrosine kinase, is associated with advanced disease stages and poor overall survival. Characteristic low oxygen tensions in HCC, so called hypoxia, promote tumor progression and metastasis and notably induce the expression of AXL. However, the impact of GAS6/AXL signaling on hypoxia-induced HCC progression and metastasis are poorly understood. In the proposed project, I will clarify the role of GAS6/AXL signaling in the hypoxia-induced initial steps of HCC metastasis such as epithelial-mesenchymal transition and invasion as well as in metastasis in vivo. Moreover, I will examine the therapeutic potential of AXL signaling blockade on interfering with the metastatic cascade. To achieve these goals, I will utilize genetic approaches to silence AXL in HCC cell lines to assess the physiological role of AXL and a high affinity soluble AXL decoy receptor to assess the therapeutic potential of AXL inhibition. The soluble AXL decoy receptor was previously developed in my host laboratory and exhibits substantially higher binding affinity to GAS6 than to the wildtype receptor AXL. Using the AXL-silenced HCC cell lines or wildtype HCC cell lines treated with the AXL inhibitor, I will analyze changes in hypoxia-induced epithelial-mesenchymal transition, invasion, and primary and metastatic HCC growth in xenografts and syngeneic allografts. Using metastasis models, I will define the impact of therapeutic AXL inhibition on the reduction of already existing metastases, and compare its efficacy with the standard of care treatment sorafenib. This is of high clinical relevance, since advanced HCC patients commonly carry metastases at the time of their diagnosis.The successful completion of the proposed project will provide preclinical data to support the use of AXL inhibitors for the treatment of advanced, metastatic HCC. This project is of high clinical relevance, since new treatment options for advanced HCC are urgently needed.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Amato Giaccia