A Novel Oral Therapeutic for Hepatocellular Carcinoma (HCC)

DESCRIPTION provided by applicant Our goal is to develop a low cost therapy for hepatocellular carcinoma HCC an important worldwide cause of cancer related death with over cases diagnosed each year year survival rates are less than and there is an urgent need for effective therapies Risk factors include chronic hepatitis viral infections cirrhosis of any cause and non alcoholic steatohepatitis NASH Because the highest burden is in developing countries low cost technologies are especially needed Using a validated mouse model of NASH related HCC in which of mice develop HCC after streptozotocin injection followed by high fat diet we recently discovered that treatment of these mice with clemizole a first generation anti histamine we found to be highly concentrated in liver led to a dramatic fold reduction in the incidence and size of HCC nodules with mice having undetectable lesions Moreover clemizole is safe and well tolerated at comparable doses in humans including in our recent studies in patients with hepatitis C Finally the concentration of clemizoe expected to be achieved in patient livers is highly toxic to human HCC cells in culture whereas it is well tolerated by primary human liver cells We now wish to translate these exciting data int a new low cost therapy for HCC by Synthesizing and determining the relative cytotoxicity against a variety of HCC cell lines mouse and human of clemizole vs its major metabolites M and M and selected analogs Determining the therapeutic potential in addition to chemoprevention of clemizole and any identified back up molecule against HCC by identifying new HCC lesions in streptozotocin high fat diet mice by CT scan prior to treatment and determining the change in lesion size and rate of new lesion formation as a function of subsequent treatment with clemizole vs potential back up vs vehicle control and Determining the mechanism of clemizoleandapos s toxicity to HCC by a characterizing the nature of HCC toxicity apoptosis vs necrosis vs autophagy b determining the role of clemizoleandapos s antihistamine activity by analyzing the HCC toxicity of a collection of antihistamines and clemizole analogs devoid of clemizoleandapos s tertiary amine and c performing a genome wide high density shRNA screen in clemizole treated HCC cell lines to identify candidate target gene s Successful accomplishment of our aims will yield in vivo proof of concept for the intended clinical indication in an appropriate validated model as well as a mechanism for clemizoleandapos s dramatic in vivo anti HCC activity Importantly our team is highly experienced in successful drug discovery and development and has the unique experience and expertise to translate our compelling preliminary data into a clinic ready therapy for the devastating disease of hepatocellular carcinoma with an exciting commercial development plan PUBLIC HEALTH RELEVANCE Our goal is to develop a low cost therapy for hepatocellular carcinoma HCC an important worldwide cause of cancer related death with over cases diagnosed each year and year survival rates less than We discovered a safe and well tolerated drug that dramatically inhibits the development of HCC in a validated mouse model and we now wish to translate these findings into a clinic ready therapy for HCC with an exciting commercial development plan