Development of Novel Targeted Therapy for Hepatocellular Carcinoma

PROJECT SUMMARYThe specific focus of this phase I application is to develop liver tissue targeting histone deacetylase inhibitorsHDACifor targeted hepatocellular carcinomaHCCtherapyHCC accounts for overof all liver cancers and is one of the most common types of malignanciesHCC is associated with a relatively lowyear survival rateand it is the third leading cause of cancer death globallySurgical resectionthe common treatment optionis limited to those patients with good liver function and early stage diseaseUnfortunatelyonly a small proportion of patients are suitable candidates for surgeryand the relapse rate is very high after surgeryLiver transplant has proven successful in treating limited cases of early stage HCC as only an even smaller proportion of patients are eligible for transplantationSystemic chemotherapy is considered to offer the most promise in the treatment of HCCThis promise became closer to reality with the FDA approval of sorafenib inHoweversorafenib extends survival in advanced HCC patients bytomonthsThereforethere continues to be an unmet medical need for safe and efficacious HCC therapeutic strategiesHCC is a complex and heterogeneous neoplasm as it results from a large number of genetic mutations and epigenetic alterationsIn particulargene silencing chromatin histone hypoacetylation play a significant role in the development and sustenance of HCCthereforenovel compounds endowed with a histone deacetylaseHDACinhibitory activity are attractive HCC therapeutic agentsOur hypothesis is that selective accumulation of HDACi within diseased tissues will enhance the therapeutic indices of HDACi and expand their efficacy to include solid tumorsToward this endwe seek to develop new HDACi which selectively accumulate in liver tissues as clinically useful targeted anti HCC agentsOur specific aims areDevelop liver targeted HDACi as novel anticancer agents against HCCAdvance liver targeted HDACi through characterization of the structural and biochemical requirements for whole cell and in vivo efficacy of lead compounds in miceWe believe that a successful implementation of the proposed studies will furnish a new class of targeted antiHCC agents and provide a foundation for the initiation of comprehensive ADMET studies during the Phase II grant period that will ultimately enable Sophia Bioscience file an Investigational New DrugINDapplication preparatory to human clinical trials PROJECT NARRATIVEHepatocellular carcinomaHCCaccounts for overof all liver cancers and is one of the most common types of malignanciesHCC is associated with a relatively lowyear survival rateand it is the third leading cause of cancer death globallyThe primary goal of the research enumerated in this proposal is to develop new liver targeting histone deacetylase inhibitors for targeted HCC treatment