Role and Biomarker Value for Plasma HGF in Susceptibility to High-Dose Radiation-Induced Liver Dysfunction
Abstract
This proposal addresses the 2018 Peer Reviewed Cancer Research Program Topic Area of “Liver Cancer.” It also addresses the Military Relevance Focus Area “Gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship that may impact mission readiness and the health and well-being of military members, Veterans, their beneficiaries, and the general public.” Liver cancer is strongly linked with male gender, poor nutrition, and repeated exposure to toxins (including radiation, chemicals, alcohol, and nicotine). While the risk for military personnel is difficult to quantify with precision, it is clear that active duty Service members are routinely exposed to these high-risk factors. In contrast to the stable and declining incidence rates for the major cancers, liver cancer shows increases in the general population, annualized at 3.6% and 2.9% for men and women, respectively, and rising death rate for both sexes in the United States (23). Thus, it is also clear that their families and other military beneficiaries are at increased risk. We will study the safe implementation of a new and potentially more efficacious modality of radiation treatment called hypofractionated radiotherapy. This modality employs larger doses of radiation in shorter periods of time and has shown potential for controlling local liver cancer growth in the vast majority (more than 90%) of the patients with tumors that cannot be surgically removed. One other potential benefit for this strategy is that it could serve as a bridge to curative liver transplantation. In this manner, hypofractionated therapy could decrease the suffering from liver cancer and increase survival for this disease, which is currently the second most frequent cause of cancer-related death worldwide. The most frequent liver cancer (>80% of cases) is hepatocellular carcinoma. Unfortunately, most patients with hepatocellular carcinoma also present with severe underlying liver damage. This characteristic can limit the use of hypofractionated radiotherapy, because patients could die due to worsening of hepatic function after radiotherapy without disease recurrence. Thus, mitigating hepatic dysfunction is the most critical issue for the implementation of this potentially transformative treatment. However, available methods for evaluation of liver damage rely on markers of worsening hepatic function during treatment, and thus cannot be used for patient or radiation dose selection. We have recently discovered a pre-treatment blood marker that could potentially predict the susceptibility for radiation-induced liver damage in hepatocellular carcinoma patients. This growth factor, called hepatocyte growth factor (HGF), can be readily measured in blood using a standardized protocol and a patented method at any medical center in the United States, and can be used for selection of hepatocellular carcinoma patients and dose of radiotherapy. Based on compelling preliminary evidence from previous clinical studies and experiments in animal models, our goal here is to validate the utility of this marker in an ongoing large clinical trial in which patients with hepatocellular carcinomas that cannot be resected are randomized to one of two hypofractionated radiotherapy modalities. The specificity of this marker will be confirmed by evaluating it in hepatocellular carcinoma patients undergoing hypofractionated radiotherapy versus other standard therapies such as transarterial chemoembolization (TACE) or surgical resection. Another goal is to use animal models to examine why elevated blood HGF is a biomarker. Our hypothesis here is that there is a causality between HGF signaling pathway activation and liver damage, which could be uncovered using preclinical models of liver damage and hepatocellular carcinoma in mice. Potential Impact: Revealing the role of HGF in liver damage could lead in the short term to an objectively measurable pretreatment marker to determine
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910284
Entities
People
- Gabriel Duda
Organizations
- Massachusetts General Hospital
- United States Army