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Faculty Biography For:

Shaun Xiaoliu Zhang
Director, Center for Nuclear Receptors and Cell Signaling; M.D. Anderson Professor
M.D., Tongji Medical College, HUST; Ph.D., Australian National University

Biology and Biochemistry Department
University of Houston
Houston, Texas 77204-5001

Office: SERC Room 3005
Phone: 832-842-8842
Curriculum Vitae  

Cancer virotherapy, immunotherapy and gene therapy
The major goals of our research are to develop novel biotherapies for the unmet need in cancer treatment, especially for solid tumors. Specifically, our research efforts are mainly focused on the following areas: 1) Cancer virotherapy, 2) Cancer immunotherapy, 3) Exploration of the newly developed TALNE technology for studies in discovering novel cancer therapies and for understanding tumor metastatic mechanisms, and 4) Establishment of new tumor models.

Despite recent progress in basic research and clinical care, patients with many malignant diseases still have very poor prognoses. Thus, novel therapeutic strategies are urgently needed. We have been pursuing the idea of modifying a benign human virus through genetic approaches to make it specifically kill tumor cells. This idea is based on the fact that viruses naturally infect and grow inside living cells in our body, a process that leads to cell destruction and the spread of infection throughout a tissue. However, the very properties that enable them to cause diseases are exactly needed for killing tumor cells, and cancer virotherapy would be feasible if they can be harnessed to specifically target malignant cells. We have chosen herpes simplex virus (HSV), a well-studied human virus whose natural infection causes cold sore, for the construction of an oncolytic virus. We have genetically modified a type II HSV in such a way that it can selectively seek tumor cells with an activated Ras signaling pathway for destruction. We have designated this oncolytic HSV as FusOn-H2. Ras signaling pathway is a key regulator of normal cell growth and malignant transformation. It usually remains inactive in normal cells but is frequently activated aberrantly in many human tumors. Thus, FusOn-H2 can be applied to the treatment of many types of solid tumors. During the construction of FusOn-H2, we have also built several extra killing mechanisms into the virus to enable it to induce cell membrane fusion (syncytium formation) and apoptosis in tumor cells. As the consequence, FusOn-H2 has shown potent antitumor activities in several tumor models, including breast cancer, ovarian cancer, pancreatic cancer and prostate cancer, without notable toxicity. Efforts are currently underway to further improve this novel therapy, with the aim of translating it into clinical application in the near future.

Immunotherapy has shown considerable promises as a useful cancer treatment modality, as the induced antitumor immune responses have the potential to eradicate locally invasive or metastatic tumors that are difficult to manage with conventional agents. Cancer vaccines derived from whole tumor cells have a major advantage over those based on identified tumor antigens, in that a single vaccine preparation would, in principle, include the entire antigenic repertoire of tumor cells. In situ tumor destruction by an oncolytic virus such as FusOn-H2 represents a simple yet an attractive way of whole tumor cell vaccination, and has several advantages over the traditional way of ex vivo preparation of whole tumor vaccines. First, in the traditional approaches, whole tumor cell vaccines are prepared from tumor cells that have undergone extensive in vitro expansion and other manipulations, which may alter the qualitative and/or quantitative profile of tumor antigens. Hence, the generated immune responses from these vaccines may not readily recognize the original tumor cells in the cancer patients. In situ tumor destruction by an oncolytic virus releases tumor antigens in their native form and configuration. Second, ex vivo approaches frequently use allogeneic tumor cells, while oncolysis from virotherapy, in principle, offers a means of personalized vaccination. Indeed, work from our own lab has shown that destruction of syngeneic murine tumors by FusOn-H2 induces effective antitumor immunity that can clear metastatic tumor nodules in distant organs such as the lung. Another strategy that our lab is currently exploring in cancer immunotherapy is to modify the T cell receptor (TCR) in naïve lymphocytes to instantly convert them into tumor killers. The strategy is to replace the natural binding domain of TCR with a single chain antibody that recognizes a tumor-associated antigen. The modified TCR will be engrafted naïve T cells by gene transduction techniques and the modified T cells will be injected back to the host to allow them to attack tumor cells. We are also investigating the effect of regulatory T cells on the adoptively transferred T effector cells and will design counter measures to negate their inhibitory effect.

One new research project that has just been initiated in the lab is to explore the recently developed TALEN (Transcription Activator-Like Effector Nucleases) for genetic studies and cancer research. This technology is based on the unique property of the transcription activator-like effector (TALE) found within plant pathogenic Xanthomonas bacteria, which can bind to sequence-specific regions to regulate specific gene expression. The mystery of the ability of a TALE to specifically bind to a particular DNA sequence has been recently decoded. This factor apparently contains a highly repetitive DNA-binding domain with a tandem array of repeat monomers each consisting of ~34 amino acids. Binding of TALEs to DNA is governed by a simple code coordinated by the 12th and 13th amino acids of each repeat module, known as the repeat variable di-residue (RVD). The RVD of each repeat monomer recognizes a single DNA base and has been deciphered as the following code: NI = A, HD = C, NG = T, NN = G/A. Thus, preferential binding of a RVD to a single DNA base provides a highly predictable and simple code for engineering novel TALEs which can bind to precise, user-defined DNA targets. Engineered TALEs and TALENs are chimeric proteins that can be fused with any functional, effector domain and subsequently, used to modulate and/or alter gene function. We are currently using this technology for both in vitro and in vivo studies to understand therapeutic responses and metastatic mechanisms of malignant cells.

Another ongoing project in the lab is to develop new tumor models, in particular the metastatic models of breast cancer and pancreatic cancer. The main purpose of this project is for in vivo studies, by taking the advantage of recent improvement in the sensitivity of in vivo imaging techniques. We will tag tumor cells with marker genes whose products can be monitored live by in vivo imaging apparatus. The established tumor models are expected to be extremely useful in facilitating both mechanistic studies of tumor metastasis and therapeutic evaluation of novel tumor biotherapies.

Xinping Fu, Armando Rivera, Lihua Tao and Xiaoliu Zhang (2013). Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors, and increase nanoparticle delivery. International Journal of Cancer. In revision.

Xinping Fu, Lihua Tao, Armando Rivera, Bart De Geest and Xiaoliu Zhang (2012). Construction of an oncolytic herpes simplex virus that precisely targets hepatocellular carcinoma cells. Molecular Therapy. 20(2):339-46. doi: 10.1038/mt.2011.265.

Xinping Fu, Armando Rivera, Lihua Tao and Xiaoliu Zhang (2012). Incorporation of the B18R gene of vaccinia virus into an oncolytic HSV can significantly improve its antitumor activity. Molecular Therapy. 2012 Jun 12. doi: 10.1038/mt.2012.113. [Epub ahead of print].

Xinping Fu, Lihua Tao, Armando Rivera1 and Xiaoliu Zhang (2011). Rapamycin enhances the activity of oncolytic herpes simplex virus against tumor cells that are resistant to virus replication. Int J. Cancer. 129(6):1503-1510.

Xinping Fu, Lihua Tao and Xiaoliu Zhang (2011). Virotherapy induces massive infiltration of neutrophils in a subset of tumors defined by a strong endogenous interferon response activity. Cancer Gene Ther. 18(11):785-794. doi: 10.1038/cgt.2011.

Xinping Fu, Lihua Tao and Xiaoliu Zhang (2010). A Short Polypeptide from HSV-2 ICP10 gene can Induce Antigen Aggregation and Autophagosomal Degradation for Enhanced Immune Presentation. Human Gene Ther. 21:16871696.

Xinping Fu, Lihua Tao and Xiaoliu Zhang (2010). A Short Polypeptide from HSV-2 ICP10 gene can Induce Antigen Aggregation and Autophagosomal Degradation for Enhanced Immune Presentation. Human Gene Ther. 21:16871696.

Xinping Fu, Lihua Tao, Armando Rivera, Shana Williamson, Xiao-Tong Song, Nabil Ahmed and Xiaoliu Zhang (2010). A simple and sensitive method for measuring tumor-specific T cell cytotoxicity. PLoS ONE. 5(7): e11867.

Hontao Li, Zihua Zeng, Xinping Fu and Xiaoliu Zhang (2007). Co-administration of an HSV-2-based oncolytic virus with cyclophosphamide leads to synergistic antitumor effect and induction of tumor-specific immune responses in the Lewis Lung tumor model. Cancer Res. 67, 7850-7855.

Fu X, Tao L, Prigge J, Cai R, Zhang X. (2006). A mutant type 2 herpes simplex virus deleted for the protein kinase domain of the ICP10 gene is a potent oncolytic virus. Mol. Ther. 13(5): 882-890.

Mikihito Nakamori, Xinping Fu, Raphael Rousseau, Si-Yi Chen and Xiaoliu Zhang (2004). Destruction of nonimmunogenic mammary tumor cells by a fusogenic oncolytic herpes simplex virus induces potent antitumor immunity. Mol. Ther. 9(5): 658-665.

X. Fu, L. Tao, A. Jin, R. Vile, M.K. Brenner and X. Zhang (2003). Expression of fusogenic membrane glycoprotein by an oncolytic herpes simplex virus provides potent synergistic anti-tumor effect. Mol. Ther. 7(6): 748-54.

X. Fu, L. Tao and X. Zhang (2003). The promoter of the strictly late viral gene UL38 is a tumor specific in the context of an oncolytic herpes simplex virus. Gene Ther. 10(17): 1458-1464.

X. Fu and X. Zhang (2002). Potent Systemic Anti-tumor Activity from an Oncolytic Herpes Simplex Virus of Syncytial Phenotype. Cancer Res. 62(8): 2306-2312.