Nucleostemin: A New Tumor Addictive Mechanism, Outcome Predictor, and Therapeutic Target for Hepatocellular Carcinoma
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abstract
Liver cancer is projected to become the third leading cause of cancer-related death by 2030. Moreover, it has created major issues of health disparity in the US, affecting disproportionately the Mexican American population in south Texas. To date, patients with unresectable liver cancer remain almost untreatable, with a 5-year survival rate below 15%. The challenges in treating unresectable liver cancer reside in its high resistance to chemo/radiation therapies and diverse underlying causes. Recent studies, which include some of ours, have determined that in spite of the many events that drive tumor development, they all seem to converge on a few protective mechanisms that allow tumor cells ... Read More Liver cancer is projected to become the third leading cause of cancer-related death by 2030. Moreover, it has created major issues of health disparity in the US, affecting disproportionately the Mexican American population in south Texas. To date, patients with unresectable liver cancer remain almost untreatable, with a 5-year survival rate below 15%. The challenges in treating unresectable liver cancer reside in its high resistance to chemo/radiation therapies and diverse underlying causes. Recent studies, which include some of ours, have determined that in spite of the many events that drive tumor development, they all seem to converge on a few protective mechanisms that allow tumor cells to survive the highly stressed malignant states, and one of them is controlled by nucleostemin (NS). My group has been the leading force in studying NS as a key stem cell self-renewal factor. The objective of this proposal is to elucidate the novel mechanism of this NS-mediated tumor addiction for liver cancer and a new role of NS depletion in sensitizing liver cancer to antibody-based therapies. Two specific aims will be pursued. First, we will study a novel mechanism by which NS promotes the repair of liver cancer genome in areas previously thought to be inaccessible. Second, we will study the new role of NS as a tumor addiction and an immune-sensitizer in a mouse liver cancer model. Upon completion, we expect to have determined a convergent tumor addiction target universally needed by most liver cancers to remain alive at the advanced stage, regardless of their different etiologies and pathology. Future benefits include using NS as an outcome predictor and therapeutic classifier, as well as designing new targeted therapies to increase the response of patients with unresectable liver cancer to antibody-based therapies, which should ameliorate the liver cancer-related health disparity issue in Texas.
