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, Ivanov, Sarkar, Spiegel, Wang and Windle.
Praveen Bhoopathi, Ph.D.
Swadesh Das, Ph.D.
Luni Emdad, M.B.B.S., Ph.D.
Mitchell Menezes, Ph.D.
Anjan Pradhan, Ph.D.
Xuening Shen, M.D.
Senior Laboratory Technician
Sarmistha Talukdar, Ph.D.
Bainan Wu, Ph.D.
SBMRI Postdoctoral Fellow
Kegelman TP, Das SK, Menezes ME, Emdad L, Dasgupta S, Bruce JN, Dent P, Pellecchia M, Sarkar D, and Fisher PB. MDA-9/syntenin is a key regulator of glioma pathogenesis. Neuro-Oncol. 2013, in press.
Bhutia SK, Das SK, Azab B, Menezes ME, Dent P, Wang XY, Sarkar D, and Fisher PB. Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24. Int J Cancer. 2013, 133:2726-2736.
Das SK, Bhutia SK, Azab B, Kegelman TP, Peachy L, Santhekadur PK, Dasgupta S, Dash R, Dent P, Grant S, Emdad L, Pellecchia M, Sarkar D, and Fisher PB. MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma. Cancer Res. 2013, 73:844-854.
Dasgupta S, Menezes ME, Das SK, Emdad L, Janjic A, Bhatia S, Mukhopadhyay ND, Shao C, Sarkar D, and Fisher PB. Novel role of MDA-9/syntenin in regulating urothelial cell proliferation by modulating EGFR signaling. Clin Cancer Res. 2013, 19:4621-4633.
Chen D, Siddiq A, Emdad L, Rajasekaran D, Gredler R, Shen XN, Santhekadur PK, Srivastava J, Robertson CL, Dmitriev I, Kashentseva EA, Curiel DT, Fisher PB, and Sarkar D. Insulin-like growth factor-binding protein-7 (IGFBP7): a promising gene therapeutic for hepatocellular carcinoma (HCC). Mol Ther. 2013, 21:758-766.
Sarkar D and Fisher PB. AEG-1/MTDH/LYRIC: clinical significance. Adv Cancer Res. 2013, 120:39-74.
Wang S, Noberini R, Stebbins JL, Das S, Zhang Z, Wu B, Mitra S, Billet S, Fernandez A, Bhowmick NA, Kitada S, Pasquale EB, Fisher PB, Pellecchia M. Targeted delivery of paclitaxel to EphA2-expressing cancer cells. Clin Cancer Res. 2013, 19:128-137.
Das SK, Bhutia SK, Sokhi UK, Azab B, Su ZZ, Boukerche H, Anwar T, Moen EL, Chatterjee D, Pellecchia M, Sarkar D, and Fisher PB. Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma. Cancer Res. 2012, 72:6217-6226.
Guo C, Yi H, Yu X, Zuo D, Qian J, Yang G, Foster BA, Subjeck JR, Sun X, Mikkelsen RB, Fisher PB, and Wang XY. In situ vaccination with CD204 gene-silenced dendritic cell, not unmodified dendritic cell, enhances radiation therapy of prostate cancer.Mol Cancer Ther. 2012, 11:2331-2341.
Srivastava J, Siddiq A, Emdad L, Santhekadur PK, Chen D, Gredler R, Shen XN, Robertson CL, Dumur CI, Hylemon PB, Mukhopadhyay ND, Bhere D, Shah K, Ahmad R, Giashuddin S, Stafflinger J, Subler MA, Windle JJ, Fisher PB, and Sarkar D. Astrocyte elevated gene-1 promotes hepatocarcinogenesis: novel insights from a mouse model. Hepatology. 2012, 56:1782-1791.
Sano R, Hou YC, Hedvat M, Correa RG, Shu CW, Krajewska M, Diaz PW, Tamble CM, Quarato G, Gottlieb RA, Yamaguchi M, Nizet V, Dahl R, Thomas DD, Tait SW, Green DR, Fisher PB, Matsuzawa S, and Reed JC. Endoplasmic reticulum protein BI-1 regulates Ca²⁺-mediated bioenergetics to promote autophagy. Genes Dev. 2012, 26:1041-1054.
Naydenov NG, Harris G, Brown B, Schaefer KL, Das SK, Fisher PB, and Ivanov AI. Loss of soluble N-ethylmaleimide-sensitive factor attachment protein α (αSNAP) induces epithelial cell apoptosis via down-regulation of Bcl-2 expression and disruption of the Golgi. J Biol Chem. 2012, 287:5928-5941.
Dash R, Azab B, Quinn BA, Shen X, Wang XY, Das SK, Rahmani M, Wei J, Hedvat M, Dent P, Dmitriev IP, Curiel DT, Grant S, Wu B, Stebbins JL, Pellecchia M, Reed JC, Sarkar D, and Fisher PB. Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity. Proc Natl Acad Sci USA. 2011, 108:8785-8790.
Lee SG, Kim K, Kegelman TP, Dash R, Das SK, Choi JK, Emdad L, Howlett EL, Jeon HY, Su ZZ, Yoo BK, Sarkar D, Kim SH, Kang DC, and Fisher PB. Oncogene AEG-1 promotes glioma-induced neurodegeneration by increasing glutamate excitotoxicity. Cancer Res. 2011, 71:6514-6523.
Dash R, Azab B, Shen XN, Sokhi UK, Sarkar S, Su ZZ, Wang XY, Claudio PP, Dent P, Dmitriev IP, Curiel DT, Grant S, Sarkar D, and Fisher PB. Developing an effective gene therapy for prostate cancer: New technologies with potential to translate from the laboratory into the clinic. Discov Med. 2011, 11:46-56.
Bhang HE, Gabrielson KL, Laterra J, Fisher PB, and Pomper MG. Tumor-specific imaging through progression elevated gene-3 promoter-driven gene expression. Nat Med. 2011, 17:123-129.
Bhutia SK, Kegelman TP, Das SK, Azab B, Su ZZ, Lee SG, Sarkar D, and Fisher PB.Astrocyte elevated gene-1 induces protective autophagy. Proc Natl Acad Sci USA. 2010, 107:22243-22248.
Dash R, Bhutia SK, Azab B, Su ZZ, Quinn BA, Kegelman TP, Das SK, Kim K, Lee SG, Park MA, Yacoub A, Rahmani M, Emdad L, Dmitriev IP, Wang XY, Sarkar D, Grant S, Dent P, Curiel DT, and Fisher PB. mda-7/IL-24: a unique member of the IL-10 gene family promoting cancer-targeted toxicity. Cytokine Growth Factor Rev. 2010, 21:381-391.
Das SK, Sokhi UK, Bhutia SK, Azab B, Su ZZ, Sarkar D, and Fisher PB. Human polynucleotide phosphorylase selectively and preferentially degrades microRNA-221 in human melanoma cells. Proc Natl Acad Sci USA. 2010, 107:11948-11953.
Yoo BK, Emdad L, Gredler R, Fuller C, Dumur CI, Jones KH, Jackson-Cook C, Su ZZ, Chen D, Saxena UH, Hansen U, Fisher PB, and Sarkar D. Transcription factor Late SV40 Factor (LSF) functions as an oncogene in hepatocellular carcinoma. Proc Natl Acad Sci USA. 2010, 107:8357-8362.
Hamed HA, Yacoub A, Park MA, Eulitt PJ, Dash R, Sarkar D, Dmitriev IP, Lesniak MS, Shah K, Grant S, Curiel DT, Fisher PB, and Dent P. Inhibition of multiple protective signaling pathways and Ad.5/3 delivery enhances mda-7/IL-24 therapy of malignant glioma. Mol Ther. 2010, 18:1130-1142.
Emdad L, Lee SG, Su ZZ, Jeon HY, Boukerche H, Sarkar D, and Fisher PB. Astrocyte elevated gene-1 (AEG-1) functions as an oncogene and regulates angiogenesis.Proc Natl Acad Sci USA. 2009, 106:21300-21305.
Tormo D, Checińska A, Alonso-Curbelo D, Pérez-Guijarro E, Cañón E, Riveiro-Falkenbach E, Calvo TG, Larribere L, Megías D, Mulero F, Piris MA, Dash R, Barral PM, Rodríguez-Peralto JL, Ortiz-Romero P, Tüting T, Fisher PB, Soengas MS. Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells. Cancer Cell. 2009, 16:103-114.
Barral PM, Sarkar D, Su ZZ, Barber GN, DeSalle R, Racaniello VR, and Fisher PB. Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: key regulators of innate immunity. Pharmacol Ther. 2009, 124:219-234.
Yoo BK, Emdad L, Su ZZ, Villanueva A, Chiang DY, Mukhopadhyay ND, Mills AS, Waxman S, Fisher RA, Llovet JM, Fisher PB, and Sarkar D. Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J Clin Invest. 2009, 119:465-477.
Boukerche H, Su ZZ, Prévot C, Sarkar D, and Fisher PB. mda-9/Syntenin promotes metastasis in human melanoma cells by activating c-Src. Proc Natl Acad Sci USA. 2008, 105:15914-15919.
Sauane M, Su ZZ, Gupta P, Lebedeva IV, Dent P, Sarkar D, and Fisher PB. Autocrine regulation of mda-7/IL-24 mediates cancer-specific apoptosis. Proc Natl Acad Sci USA. 2008, 105:9763-9768.
Gao P, Sun X, Chen X, Wang Y, Foster BA, Subjeck J, Fisher PB, and Wang XY. Secretable chaperone Grp170 enhances therapeutic activity of a novel tumor suppressor, mda-7/IL-24. Cancer Res. 2008, 68:3890-3898.
Lee SG, Su ZZ, Emdad L, Gupta P, Sarkar D, Borjabad A, Volsky DJ, and Fisher PB. Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. J Biol Chem. 2008, 283:13116-13123.
Gupta P, Emdad L, Lebedeva IV, Sarkar D, Dent P, Curiel DT, Settleman J, and Fisher PB. Targeted combinatorial therapy of non-small cell lung carcinoma using a GST-fusion protein of full-length or truncated MDA-7/IL-24 with Tarceva. J Cell Physiol. 2008, 215:827-836.
Sarkar D, Lebedeva IV, Su ZZ, Park ES, Chatman L, Vozhilla N, Dent P, Curiel DT, and Fisher PB. Eradication of therapy-resistant human prostate tumors using a cancer terminator virus. Cancer Res. 2007, 67:5434-5442.
Lee SG, Su ZZ, Emdad L, Sarkar D, and Fisher PB. Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc Natl Acad Sci USA. 2006, 103:17390-17395.
Fisher PB. Is mda-7/IL-24 a "magic bullet" for cancer? Cancer Res. 2005, 65:10128-10138.
Sarkar D, Su ZZ, Vozhilla N, Park ES, Randolph A, Valerie K, and Fisher PB. Targeted virus replication plus immunotherapy eradicates primary and distant pancreatic tumors in nude mice. Cancer Res. 2005, 65:9056-9063.
Sarkar D, Su ZZ, Vozhilla N, Park ES, Gupta P, and Fisher PB. Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice. Proc Natl Acad Sci USA. 2005, 102:14034-14039.
Su ZZ, Sarkar D, Emdad L, Duigou GJ, Young CS, Ware J, Randolph A, Valerie K, and Fisher PB. Targeting gene expression selectively in cancer cells by using the progression-elevated gene-3 promoter. Proc Natl Acad Sci USA. 2005, 102:1059-1064.
Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, and Fisher PB. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005, 433:73-77.