Mechanisms of Acquired Resistance to Sorafenib in Hepatocellular Carcinoma

The scientific objective of this proposed project is to uncover ways in which primary liver cancer (hepatocellular carcinoma, or HCC) escapes the effectiveness of an established treatment, sorafenib, which will enable us to develop new, more effective therapies for this disease. Our rationale is that by using an integrated strategy that combines information from human tumors with novel animal models to test candidate drugs in a systematic fashion, we can accelerate the discovery of novel therapies. HCC is a catastrophic cancer that arises in livers of patients who have chronic inflammation due to viral infection, fat accumulation, alcohol abuse, and other causes. The disease disproportionately affects military Veterans and active duty military Service members, who are at 15 times greater risk than the general population. Currently, the only potential for cure of HCC is to diagnose the cancer at an early stage when it can be removed surgically or through physical ablation using a probe inserted directly into the tumor. Therefore, the large majority of patients have few treatment options, and the only approved medication, sorafenib, can slow progression for a limited time, but never cures the disease. Importantly, as with many cancers, HCCs typically evolve mechanisms to escape the efficacy of sorafenib over time. We propose to conduct a comprehensive, sophisticated, and unique study to uncover mechanisms of sorafenib resistance in order to accelerate the development of new drugs or drug combinations to prevent this from occurring. This effort will provide the benefit of improving the outcome of patients with this cancer and bringing new drugs to these patients faster than ever. There are no risks to patients that directly attributable to the studies proposed in this application. Should new drugs be tested, however (which is beyond the scope of this application), these agents could lead to unwanted toxicities or side effects. As noted, however, such clinical studies are not a direct component of this application. In pursuing this project, we will exploit state-of-the-art methods to uncover unique mutations in tumors that are resistant to sorafenib, and then grow these tumors in mice to test novel drug combinations and also explore how the surrounding tissue might contribute to drug resistance. This approach will enable us to uncover new targets and test novel therapies in an expedited manner. The ultimate applicability of this research will be widespread and could improve the outlook for all patients with HCC by identifying novel targets for treatment that can be combined with or replace sorafenib to avoid drug resistance. Following the completion of this 3-year project, we anticipate the discovery of new drug targets that will enable us to test their efficacy in animal models and then quickly translate this information into new clinical trials within 4 to 5 years. As noted above, the disproportionate impact of HCC on active duty Service members, their families, and other military beneficiaries means that advances will rapidly improve the outlook and hopes of these individuals. Thus, the likely contribution of this effort will be to create new treatment options for patients with advanced HCC, which is a major Peer Reviewed Cancer Research Program topic area.