Jacob Lab

Sam Jacob  Samson Jacob, PhD
William and Joan Davis Professor of Cancer Research
Professor of Molecular & Cellular Biochemistry, and Medicine
Co-Director, Experimental Therapeutics Program
The Ohio State University Comprehensive Cancer Center

Dr. Jacob’s research program focuses on three areas: (1) Epigenetic silencing of tumor suppressors at different stages of tumorigenesis using cells in culture and  animal models with emphasis on mechanisms and therapeutic interventions in human cancer; (2) Delineating the role of microRNAs in the initiation and progression of hepatocellular carcinoma and breast cancer, and in resistance to potent anticancer drugs, and applications in therapy; and (3) Elucidating  the role of metallothioneins, the  free radical scavengers, in protecting liver from exposure to tumor-inducing agents using animal models.

Epigenetic silencing of tumor suppressor genes: The majority of the tumor suppressor genes are silenced by epigenetic mechanisms that include promoter methylation, specific histone modifications and chromatin remodeling. This mechanism provides an alternate approach to treat cancer by re-activating the silenced tumor suppressor genes by agents that restore normal cellular phenotype - epigenetic therapy. We have shown that the gene encoding a membrane-bound (receptor-type) protein tyrosine phosphatase (PTPRO) is silenced by promoter methylation in hepatocellular carcinoma (HCC), breast and lung cancer as well as chronic lymphocytic leukemia (CLL). We have identified specific substrates of PTPRO that exhibit altered phosphorylation states in cancer, resulting in  aberrations in signaling pathways leading to enhanced tumorigenesis.  We have demonstrated that PTPRO can be re-expressed in tumors by established and novel DNA hypomethylating agents. Currently, we are exploring other PTPRO substrates, their phosphorylation states in cancer and the therapeutic advantages of re-activating this gene as well as other epigenetically silenced novel tumor suppressor genes in CLL and HCC using tumor-specific animal models.

Delineating the role of microRNAs ( miRs) in tumorigenesis and applications in therapy:  We are studying the differential expression of microRNAs (miRs) at early stages of heapatocarcinogenesis using two  mouse models, one  that mimics non-alcoholic steatohepatitis (NASH)-induced HCC that has shown increased incidence in Western countries , and another model that induces HCC upon exposure to DEN ( diethyl nitrosamine) . miR microarray analysis followed by real time RT-PCR showed that a few miRs that  target mRNAs for specific tumor suppressors and oncoproteins, are  up-regulated and down-regulated, respectively,  weeks before preneoplastic nodule formation. We are exploring the possibility of reversing the tumorigenic process by altering specific miR expression using anti-miRs (for up-regulated miRs) or miR mimetics (for down-regulated miRs) specifically targeted to liver using different delivery systems including nanoparticles. This project is co-directed by Kalpana Ghoshal, PhD.

Another project led by Kalpana Ghoshal, PhD usesConditional miR-122 knock-out mice to study its role in liver pathogenesis.  Previous study initiated by Dr. Ghoshal has shown that the level miR-122, the most abundant miR in normal liver, is drastically reduced in several HCC cell lines as well as primary human HCC. The miR-122 KO mice are invaluable tool to study how altered expression of liver-specific miR can alter the liver phenotype and predisposes it to tumorigenesis. This study will also explore the potential restoration of normal liver phenotype by miR-122 mimetic therapy in animal models and extend it to primary human HCC in collaboration with the clinical researchers.

A project led by Sarmila Majumder, PhD has shown that miR-221/222 expression was significantly elevated in breast cancer resistant to tamoxifen, the most commonly used drug in the treatment of this cancer, with concomitant down-regulation of the cell cycle inhibitor p27.  These miRs were also significantly up-regulated in HER2/neu-positive primary human breast cancer tissues that are known to be resistant to endocrine therapy. Further, ectopic expression of these miRs rendered the drug-sensitive cells resistant to tamoxifen. Dr. Majumder is now elucidating  the mechanism for the increased expression of these miRs in the resistant cell lines  and a large cohort of primary resistant  human breast cancer samples , and other mechanism(s)  by which the up-regulated miRs cause tamoxifen resistance.  This study will also explore the therapeutic application of anti-miR221/222 in reversing the drug resistance and restoring normal breast phenotype.

Elucidating the role of metallothionein in progression of liver cancer: Metallothioneines (MT) are heavy metal and free radical scavenger proteins. We have shown that the genes encoding the two major isoforms of this protein, MT-I and MT-II, are suppressed in both rodent and human liver tumors. We are studying the role of MT in HCC using MT knockout mice (MTKO) where HCC was induced by DEN treatment. Increased incidences and progression of liver tumors were observed in the MTKO mice compared to the wild type mice, exhibiting a close relationship between differential activation of tumor promoting gene and increased redox stress in the MTKO mice. We are exploring the possibility of reversing the tumorigenic process by adenovirus mediated delivery of the relatively small MT proteins at different stages of tumorigenesis in the DEN induced model or other genetic models of  HCC, and elucidating the molecular mechanism for the MT-mediated reversal of liver tumorigenesis.

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) 460 W. 10th Avenue, Columbus, OH 43210 Phone: 1-800-293-5066 | Email: jamesline@osumc.edu