Laboratory of Paul B. Fisher, M.Ph., Ph.D.
Dr. Fisher’s laboratory focuses on understanding the molecular and biochemical basis of cancer etiology and progression with emphasis on translating this information to develop improved methods for diagnosing, staging and treating cancer. Additionally, research efforts are being expended to define new molecules to treat neurodegeneration and viral-mediated infectious diseases.
His laboratory has pioneered several molecular approaches, including rapid subtraction hybridization (RASH), complete open reading frame (C-ORF) technology and reciprocal subtraction differential RNA display (RSDD), resulting in the identification and cloning of several originally novel genes involved in cell growth, differentiation, innate immunity, response to viral infection, senescence, tumor progression/metastasis and cancer-specific apoptosis induction. Current studies are focusing on defining the roles of miRNA in regulating cell functions, particularly their roles in mediating cancer development and progression.
Specific genes discovered and cloned in the Fisher laboratory that are of note include: (1) melanoma differentiation associated gene-6 (mda-6), the cyclin-dependent kinase inhibitor p21; (2) mda-7/interleukin-24 (IL-24), a unique member of the IL-10 gene family that selectively induces apoptosis in cancer cells in vitro, in vivo in animal models and in a Phase I clinical trial; (3) mda-5, a distinctive double-stranded RNA pattern recognition protein that is a key regulator of innate immunity; (4) mda-9/syntenin, a direct regulator of cancer metastasis; (5) human polynucleotide phosphorylase (hPNPaseold-35), an evolutionary conserved enzyme that induces cellular senescence and apoptosis and can target specific mRNAs, such as c-myc, and microRNAs, such as miRNA-221, for degradation; and (6) astrocyte elevated gene-1 (AEG-1) upregulated in more than 95 percent of brain cancers and numerous additional cancers, an oncogene with unique properties including promotion of tumor cell invasion.
Current projects in Dr. Fisher’s laboratory are directed toward understanding the mechanism of action of mda-7/IL-24, mda-5, mda-9/syntenin, hPNPaseold-35 and AEG-1. Studies are also in progress to create and evaluate transgenic and knockout animal models displaying cancer-enhanced or cancer-suppressed phenotypes to study the roles of novel genes in vivo.
Additionally, the Fisher laboratory has developed therapeutic adenoviruses that selectively replicate in cancer cells while producing a therapeutic gene product, either interferon gamma or mda-7/IL-24, referred to as cancer terminator viruses (CTVs). Experiments in multiple human tumor models in vitro and in vivo in animals indicate that the CTVs have significant therapeutic activity against human breast cancer, therapy-resistant prostate cancer, pancreatic carcinomas, ovarian carcinomas, colorectal carcinomas, malignant gliomas and metastatic human melanomas. Potential clinical trials are contemplated for these therapeutic reagents, initially in patients with recurrent GBM.
Another area of emphasis in the Fisher laboratories involves the use of cancer-specific or cancer-selective promoters to effectively image cancers and their metastases. Proof-of-principle for this approach has come from studies using the progression elevated gene-3 promoter (PEG-Prom), which displays robust expression in virtually all cancers tested, with minimal expression in normal cells. This promoter when linked to a luciferase or HSV-Tk gene has been used to image metastases in animal models containing human metastatic cancer cells. Newer promoters in the pipeline are now being characterized that may provide an even further refinement in detection of tumors and metastases in vivo. Research is also being directed to combine both selective cancer imaging with targeted delivery of a therapeutic, a process termed “theranostics”. These studies have high potential to be translated from the laboratory into the clinic (bench-to-bedside) to more effectively diagnose and treat cancer. Specific aspects of these studies are being conducted in collaboration with scientists at Johns Hopkins University Medical Center in Baltimore, Md.
In the area of neurodegeneration, studies are aimed at elucidating the role of glutamate transport in mediating neurodegeneration and defining ways of correcting this process. The Fisher laboratory cloned the promoter region for the major gene in astrocytes involved in glutamate transport, i.e., the excitatory amino acid transporter-2 (EAAT2). The EAAT2-Prom is downregulated by the oncogene AEG-1 in malignant glioma and may contribute to the neuronal toxicity observed in patients with this aggressive cancer. Studies are using the EAAT2-Prom to identify small molecules capable of regulating glutamate transport. This research has significant potential to define ways of more effectively treating and potentially protecting from severe neurodegenerative diseases, including amyotrophic lateral sclerosis (Lou Gehrig’s disease), Huntington’s disease and Alzheimer’s disease. Specific aspects of these studies are being conducted in collaboration with scientists at the Sanford-Burnham-Presby Medical Research Institute in La Jolla, Calif.
Studies are also employing promoter-based reporter assays, including those using the PEG-Prom, in combination with both low and high throughput screening approaches, with relevant cancer-regulating genes, to identify novel therapeutic agents for cancer therapy. Fragment- and structure-based approaches guided by NMR spectroscopy in collaboration with Dr. Pellecchia (SBPMRI) are also being used to design novel small molecule therapeutics disrupting key protein-protein interactions. These are also some primary areas of focus of the VCU Institute of Molecular Medicine (VIMM), which Dr. Fisher directs. As indicated, specific aspects of these studies are being performed in collaboration with the Sanford-Burnham-Presby Medical Research Institute (SBPMRI) in La Jolla, Calif.
Dr. Fisher collaborates with Drs. Das, Emdad, Grant, Sarkar, Spiegel, Wang and Windle.
Praveen Bhoopathi, Ph.D.
Swadesh Das, Ph.D.
Luni Emdad, M.B.B.S., Ph.D.
Padmanabhan Mannangatti, Ph.D.
Anjan Pradhan, Ph.D.
Sarmistha Talukdar, Ph.D.
Stephen Wechman, Ph.D.
Bainan Wu, Ph.D.
SBMRI Postdoctoral Fellow
Pradhan, A.K., P. Bhoopathi, L. Emdad, S. K. Das, D. Sarkar and P.B. Fisher. 2017. mda-7/IL-24 mediates cancer cell-specific death via regulation of miR-221 and the beclin-1 axis. Cancer Res., 77: 949-959.
Hu, B., L. Emdad, T.P. Kegelman, X.-N. Shen, S.K. Das, D. Sarkar, and P.B. Fisher. 2017. Astrocyte elevated gene-1 regulates beta-catenin signaling to maintain glioma stem-like stemness and self-renewal. Mol. Cancer Res., 15: 225-233.
Kegelman, T.P., B. Wu, S. K. Das, S. Talukdar, J.M. Beckta, B. Hu, L. Emdad, K. Valerie, D. Sarkar, F. Funari, W.K. Cavenee, J. Wei, A. Purves, S.K. De, M. Pellecchia and P.B. Fisher. 2017. Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin. Proc. Natl. Acad. Sci. USA., 114: 370-375.
Sarkar, S., S. Konar, N. Puvvada, S. Rajput, B.N. Prashanth, R. Rao, A. Pathak, P.B. Fisher and M. Mandal. 2017. Micellear gold nanoparticle as delivery vehicle for dual tyrosine kinase inhibitor ZD6474 for metastatic breast cancer treatment. Langmuir, 33 (31): 7649-7659.
Nitkiewicz, J., A. Borjabad, S. Morgello, J. Murray, W. Chao, L. Emdad, P.B. Fisher, M.J. Potash and D.J. Volsky. 2017. HIV induces expression of complement component C3 in astrocytes by NF-B-dependent activation of interleukin-6 synthesis. J Neuroinflammation, 14: 23.
Pradhan, A.K., L. Emdad, S.K. Das, D. Sarkar and P.B. Fisher. 2017. The enigma of miRNA regulation in cancer. Adv Cancer Res, 135: 25-52.
Bharti, R., G. Dey, I. Banerjee, K.K. Dey, S. Parida, P.B.N. Kumar, C.K. Das, I. Pal, M. Mukherjee, M. Misra, A.K. Pradhan, L. Emdad, S.K. Das, P.B. Fisher and M. Mandal. 2017. Somatostatin receptor targeted liposomes with diacerein inhibit IL-6 for breast cancer therapy. Cancer Lett., 388:292-302.
Jariwala, N., D. Rajasekaran, R.G. Mendoza, X.-N. Shen, A. Siddiq, M.A. Akiel, C.L. Robertson, M.A. Subler, J.J. Windle, P.B. Fisher, A.J. Sanyal and D. Sarkar. 2017. Oncogenic role of SND1 in development and progression of hepatocellular carcinoma. Cancer Res., 77(12): 3306-3316.
Srivastava, J., C.L. Robertson, K. Ebeid, M. Dozmorov, D. Rajasekaran, R. Mendoza, A. Siddiq, M.A. Akiel, N. Jariwala, X.-N. Shen, J.J. Windle, M.A. Subler, N.D. Mukhopadhyay, S. Giashuddin, S. Ghosh, Z. Lai, Y. Chen, P.B. Fisher, A.K. Salem, A.J. Sanyal and D. Sarkar. 2017. A Novel Role of Astrocyte Elevated Gene-1 (AEG-1) in Regulating Non-alcoholic Steatohepatitis (NASH). Hepatology, 66(2): 466-480.
Croce, C.M., and P.B. Fisher (Eds.). 2017. miRNA and cancer. Adv. Cancer Res., 135: 1-220.
Croce, C.M., and P.B. Fisher. 2017. Preface to miRNA and cancer. Adv. Cancer Res., 135: ix-xi.
Akiel, M., C. Guo, X. Li, D. Rajasekaran, R.G. Mendoza, C.L. Robertson, N Jariwala, F. Yuan, M.A. Subler, J. Windle, D.K. Garcia, Z. Lai, H.H. Chen, Y. Chen, S. Giashuddin, P.B. Fisher, X.Y. Wang XY, and D. Sarkar. 2017. IGFBP7 deletion promotes hepatocellular carcinoma. Cancer Res., 77(15): 4014-4025.
Pradhan AK, L. Emdad, S.K. Das, D. Sarkar and P.B. Fisher. 2017. The enigma of miRNA regulation in cancer. Adv. Cancer Res., 135: 25-52.
Emdad, L., S.K. Das, X.-Y. Wang, D. Sarkar and P.B. Fisher. 2017. Cancer terminator viruses (CTV): a better solution for viral therapy of cancer. J. Cellular Physiology, in press.