title: The evolving landscape of therapeutic drug development for hepatocellular carcinoma.
abstract: Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates while still conferring an overall survival benefit. Unlike other solid tumors, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered. Our group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient derived xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumors. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward.
authors.affiliation: Department of Medical Oncology, National Cancer Centre Singapore, Singapore. Electronic address: dawnchong@gmail.com.
authors.forename: Dawn Qingqing
authors.initials: DQ
authors.lastname: Chong
authors.forename: Iain Beehuat
authors.initials: IB
authors.lastname: Tan
authors.forename: Su-Pin
authors.initials: SP
authors.lastname: Choo
authors.forename: Han Chong
authors.initials: HC
authors.lastname: Toh
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D044127:Epigenesis, Genetic / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors; D010671:Phenylurea Compounds / Q000627:therapeutic use; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D009536:Niacinamide; D005346:Fibroblast Growth Factors; D000077157:Sorafenib; C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases
keywords: Therapeutic drug development; hepatocellular carcinoma