Dr. Jacob’s research program focuses on three areas:
- 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;
- 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.
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. These mechanisms provide an alternate approach to treat cancer by reactivating the silenced tumor suppressor genes via 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 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. 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. We have also generated B-cell specific PTPRO Tg mice to study the gene’s role in chronic lymphocytic leukemia in vivo.
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 hepatocarcinogenesis 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 upregulated and downregulated, 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 upregulated miRs) or miR mimetics (for downregulated miRs) targeted to liver using nanoparticle-mediated delivery systems. We are also exploring the role of miRs in altered glucose metabolism in liver cancer, and using miR-based therapeutic approaches to restore the energy metabolism and normal cellular phenotype. We have made significant progress in these areas.
Tasneem Motiwala, PhD
Huban Kutay, PhD
Kun-Yu Teng (co-adviser)
Vivek Chowdhary (co-adviser)
Kalpana Ghoshal, PhD
Associate Professor of Pathology