Antonio Sorrentino, PhD – 2011 Postdoctoral Research Fellowship Award Winner

American Liver Foundation Postdoctoral Research Fellowship Award
University of California, San Francisco, San Francisco, California

“Discovery and pre-clinical development of microRNA therapeutics targeting liver cancer.”

Liver cancer is comprised of diverse, histologically distinct, primary hepatic neoplasms including hepatocellular carcinoma (HCC), the most common type of liver cancer. HCC is amongst the top four leading causes of cancer-related death worldwide with a median survival of only six months. It affects diverse populations and has varied etiology including hepatitis viruses B and C, aflatoxin B1, and alcohol. HCCs are largely resistant to existing anticancer agents, and apart from surgical resection for early stages and liver transplantation no effective cure currently exists. Recent advances have been made in the treatment of HCC, such as the multikinase small molecule inhibitor sorafenib, which has been found to prolong survival in patients with advanced HCC by about 3 months, however novel and more effective treatments need to be developed. microRNAs (miRNAs) are a distinct class of small non coding RNAs which critically regulate gene expression by controlling endogenous mRNAs predominantly at the post-transcriptional level. A large and expanding amount of evidence point to a fundamental role of miRNAs in the temporal regulation of development in various organisms. Any molecular pathways that determine cell identity and fate can be regulated by miRNAs, and consequently mutations of individual or clustered miRNAs have been shown to lead to a multitude of developmental defects such as impaired immune responses, uncontrolled tissue-specific differentiation and stem cell deficiencies. Preliminary expression analyses demonstrated a significant deregulation of miRNAs in various malignant neoplasms, including liver cancer, however many of these studies exhibited strong discrepancies in the temporal, spatial and quantitative patterns of expression even within the same tumor types. In addition, despite the enormous potential of miRNAs as therapeutics, the biological function of individual cancer-associated miRNA molecules is only recently emerging. We recently carried out in our laboratory a genome-wide miRNA profiling of liver tumors developed from conditional mouse models of liver cancer engineered to activate individual or combinations of MYC and RAS oncogenic pathways specifically in the liver. Dr. Sorrentino found that liver tumors driven by different oncogenes and a combination of both developed tumors of different histotypes and showed distinctive miRNA signatures. He plans to investigate the functional relevance of these “oncogenic miRNA signatures” in vivo, in search of novel miRNA-based circuitries to exploit as therapeutic targets to treat liver cancer.