Heshan Sam Zhou, Ph.D.

Education:Heshan Sam Zhou, Ph.D.

B.S., Wuxi Institute of Light Industry, Wuxi, China. 1979
M. S. Hangzhou University, Hangzhou, China. 1982
Ph.D., Molecular Biology, Biology and Microbiology, University of Texas, Austin TX, 1993
Postdoctoral Fellowship, Howard Hughes Medical Institute/ Baylor College of Medicine, Houston, TX, 1998

Curriculum Vitae

Current Positions:

Associate Professor, Department of Surgery, University of Louisville School of Medicine
Member, James Graham Brown Cancer Center
Associate Member, Department of Microbiology and Immunology, University of Louisville School of Medicine

Contact Information:

Clinical Translational Research Building, Room 406
University of Louisville
505 Hancock St.
Louisville, KY 40202, USA
Phone 502-852-5745
Fax 502-852-3661
Email: hszhou01@louisville.edu

Research Description

To fight a smarter war on cancer, our lab has moved in a different direction beyond the traditional approaches. We have created a novel approach to investigate improving oncolytic virotherapy for cancers. Oncolytic virotherapy with cancer-selective replicating viruses has emerged as a new hope for cancer treatment and has been considered an attractive drug platform. The therapeutic effects of oncolytic viruses are initiated from a small number of infected cancer cells and spread the infection to surrounding tumor cells. Gene-attenuated and replication-competent adenoviruses have been applied in human clinical studies and H101, an oncolytic adenovirus, has been commercially approved for cancer treatment. Our current research projects are focused on developing a new approach to improve cancer therapies.

The major strategy to increase tumor specific replication of oncolytic adenoviruses depends on transcriptionally regulating the essential E1a gene by a tumor-specific promoter.By replacing the endogenous E1a promoter with a cellular promoter preferentially active in tumor rather than normal tissues, oncolytic viruses can carry out more selective replication in tumors. Cyclin E regulates cell growth and cyclin E overexpression is highly associated with tumorigenesis. Cyclin E overexpression occurs in more than 90% of lung, liver, and gastrointestinal cancers, and also in more than 80% of glioma/blastoma, bone, and breast cancers. Previously we have shown that cyclin E overexpression in human cancer cells is a molecular basis of selective replication of oncolytic adenoviruses. We have also reported that the cyclin E promoter is augmented in cancer cells during viral reproduction processes. The unique properties of the cyclin E promoter in virus replication indicate its potential in oncolytic vector design. Based on this, we have developed E1b-deleted Ad-cycE in which the E1a gene is under the control of the human cyclin E promoter. As the cyclin E promoter is highly active in many types of cancer cells and would be further stimulated after adenovirus infection, Ad-cycE replication can be enhanced in cancer cells. Our results revealed that Ad-cycE selectively undergoes replication in various cancer cells, significantly repressed tumor growth and prolonged survival of nude mice bearing human lung cancer xenografts.

We also investigate other approaches to enhance oncolytic virotherapy. One of the projects is to study whether indole-3-carbinol (I3C) has the potential to enhance virotherapy. I3C is a dietary supplement derived from vegetables with the potential to prevent lung tumorigenesis. Our studies have shown that I3C may be an active compound with the ability to enhance virotherapy. We have observed that I3C repressed cancer cell growth, concurrently with suppressed expression of cyclin E and its partner CDK2. Our laboratory also found that I3C enhanced cytotoxic effects of oncolytic viruses on human lung carcinoma cells by synergistic upregulation of apoptosis. Our studies suggest that the vegetable compound I3C may improve virotherapies. It is important to further verify the effect of I3C in animal tumor models.

Literature Cited:

  1. Wechman SL, Rao X-M, Gomez-Gutierrez JG, Zhou HS, McMasters KM.  The role of JNK phosphorylation as a molecular target to enhance adenovirus replication, oncolysis and cancer therapeutic efficacy.  Cancer Biology & Therapy 2018 Aug1:1-11.  doi: 10.1080/15384048.2018.1491503.  PMID:30067431.
  2. Wechman SL, Rao X-M, Cheng PH, Gomez-Gutierrez JG, McMasters KM, Zhou HS.  Development of an oncolytic adenovirus with enhanced spread ability through repeated UV irradiation and cancer selection.  Viruses 2016 Jun 14;8(6):167.  doi:10.3390/v8060167.  PMID: 27314337.  PMCID: PMC4926187
  3. Wechman SL, Rao X-M, McMasters KM, Zhou HS.  Adenovirus with DNA packaging gene mutations increased virus release.  Viruses 2016 Dec 20;8(12):333.  doi:10.3390/v8120333.  PMID: 27999391.  PMCID: PMC5192394.
  4. Cheng PH, Rao X-M, Duan X, Li XF, Egger ME, McMasters KM, Zhou HS.  Virotherapy targeting cyclin E overexpression in tumors with adenovirus-enhanced cancer-selective promoter.  Journal of Molecular Medicine (Berlin) 2015 Feb;93(2):211-23.  PMIC: 25376708.  PMCID: PMC4320008.
  5. Chen L, Cheng PH, Rao X-M, McMasters KM, Zhou HS.  Indole-3-carbinol (I3C) increases apoptosis, represses growth of cancer cells, and enhances adenovirus-mediated oncolysis.  Cancer Biology & Therapy 2014 Sep;5(9):1256-67.  PMID: 24972095.  PMCID: PMC41288687.
  6. Cheng PH, Rao X-M, McMasters KM, Zhou HS.  Molecular basis for viral selective replication in cancer cells: activation of CDK2 by adenovirus-induced cyclin E.  PLoS One  2013;8(2):e57340.  PMID: 23437375.  PMCID: PMC3577715.
  7. Rodriguez-Rocha H, Gomez-Gutierrez JG, Garcia-Garcia A, Rao X-M, Chen L, McMasters KM, Zhou HS. 2011. Adenoviruses induce autophagy to promote virus replication and oncolysis. Virology  2011 Jul 20;416(1-2):9-15.  PMID: 21575980.  PMCID: PMC3113480.
  8. Gomez-Gutierrez JG, Garcia-Garcia A, Hao H, Rao X-M, Montes de Oca-Luna R, Zhou HS, McMasters KM.  Adenovirus-mediated expression of truncated E2F-1 suppresses tumor growth in vitro and in vivo.  Cancer2010 Sep 15;116(18):4420-32.  PMID: 20549818.  PMCID: PMC4425364.
  9. Gomez-Gutierrez JG, Rao X-M, Garcia-Garcia A, Hao H, McMasters KM, Zhou HS.  Developing adenoviral vectors encoding therapeutic genes toxic to host cells: Comparing binary and single-inducible vectors expressing truncated E2F-1.  Virology 2010 Feb 20;397(2):337-45.  PMID: 20003994.  PMCID: PMC2821996.
  10. Zheng X, Rao X-M, Gomez-Gutierrez JG, Hao HY, McMasters KM, Zhou HS.   Adenovirus E1B55K region is required for inducing cyclin E expression for efficient viral DNA replication in G0-arrested cells.  Journal of Virology 2008 Apr;82(7):3415-27.  PMID: 18234796.  PMCID: PMC2268468.
  11. Rao XM, Zheng X, Waigel S, Zacharias W, McMasters K, Zhou HS.  Gene expression profiles of normal human lung cells affected by adenoviral E1B.  Virology 2006 Jul 5;350(2):418-28.  PMID: 16542696.
  12. Zheng X, Rao X-M, Snodgrass CL, McMasters KM, Zhou HS.  Selective replication of E1B55K-deleted adenoviruses depends on enhanced E1A expression in cancer cells.  Cancer Gene Therapy 2006 Jun;13(6):572-83.  PMID: 16341141.
  13. Wang X, Wang JP, Rao XM, Price JE, Zhou HS, Lachman LB.  Primeboost vaccination with plasmid and adenovirus gene vaccines control HER2/neu+ metastatic breast cancer in mice.  Breast Cancer Research 2005;7:R580-R588.  PMID: 16168101.  PMCID: PMC1242122.
  14. Rao X, Tseng MT, Zheng X, Dong Y, Jamshidi-Parsian A, Thompson TC, Brenner MK, McMasters KM, Zhou HS.  E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells.  Cancer Gene Therapy 2004 Sep;11(9):585-93.  PMID: 15338010. (The featured research article in the issue)
  15. Zhao T, Rao XM, Li L, Thompson T, McMasters KM, Zhou HS.  Adenovirus with insertion-mutated E1a selectively propagates in liver cancer cells and destroys tumors in vivo.  Cancer Research 2003 Jun 15;63(12):3073-8.  PMID: 12810631.  [ http://cancerres.aacrjournals.org/content/63/12/3073.long

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