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Dr. Shibin Zhou

M.D., Ph.D.
(410) 955-0548 (f)
Interests

Molecular Genetic Analysis of Colorectal Cancer

Titles

Associate Professor of Oncology
Director, Experimental Therapeutics
Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins

Schools\Degrees

M.D., Medicine, Beijing Second Medical University, Beijing, China Ph.D., Molecular Biology, University of Pittsburgh, Pittsburgh, Pennsylvania

Training

Postdoctoral Research Fellow in Oncology, Johns Hopkins University School of Medicine

Clinical Interests

Targeted Cancer Therapy

Research Summary

Hypoxia, a consequence of tumor cells outgrowing their blood supply, and subsequent angiogenesis are two of the hallmarks of rapidly growing solid tumors. Dr. Zhou's laboratory has been exploiting these unique pathological features for developing novel therapeutic approaches. 

The hypoxic tumor compartment poses challenges for both chemo and radiation therapies as hypoxia diminishes the therapeutic effects of chemotherapeutic agents and radiation. Conversely, this tumor compartment, hypoxic and immune-privileged, provides a unique niche for anaerobic bacteria to grow. C. novyi-NT is an attenuated strain of the anaerobic bacterium Clostridium novyi. When injected intravenously, C. novyi-NT spores are not toxic to healthy animals but can selectively germinate within and colonize tumors, resulting in massive necrosis and tumor regression. In addition to direct tumor destruction by bacterial growth, the C. novyi-NT infection elicits a potent host antitumor immune response leading to long-term cures. C. novyi-NT is considered a promising anticancer agent not only for its inherent anticancer properties, but also for its capacity to enhance other cancer therapies and to serve as a tumor-specific gene therapy vector. Dr. Zhou's laboratory has combined C.
novyi-NT spores with chemotherapeutic drugs, liposomal formulation of chemotherapeutic drugs, and radiation for the treatment of several experimental tumor models. The combination therapies showed marked improvement in efficacy over the therapies using individual agents. Dr. Zhou's group is currently generating engineered C. novyi-NT strains that are more potent and less toxic in several experimental tumor models.

In response to the increased demands for nutrients and oxygen, solid tumors establish their own vascular networks that are both structurally and physiologically different from the vasculature in normal tissues. These differences form the basis for a therapeutic approach Dr. Zhou's laboratory has been developing. Both biologic and chemical agents capable of inducing vascular responses akin to those observed in inflammatory processes enhance the selective accumulation of nanoparticles in tumors. For example, the proinflammatory cytokine TNF-alpha is able to increase the tumor to blood ratio of sterically stabilized liposomes by more than 20-fold compared to the liposomes alone. Consequently, the vascular-active agents dramatically improve the therapeutic effect of liposomes containing radioactive isotopes or chemotherapeutic agents. Dr. Zhou's group is investigating a variety of vascular-active agents for their ability to augment selective tumor accumulation of nanoparticles.

 

Journal Citations

Bettegowda, C.; Huang, X.; Lin, J.; Cheong, I.; Kohli, M.; Szabo, S.A.; Zhang, X.; Diaz, L.A., Jr.; Velculescu, V.E.; Parmigiani, G.; Kinzler, K.W.; Vogelstein, B.; Zhou, S. The genome and transcriptomes of the anti-tumor agent Clostridium novyi-NT. Nat Biotechnol. 2006 Nov 19;24:1573-1580.

Cheong, I.; Huang, X.; Bettegowda, C.; Diaz, L.A., Jr.; Kinzler, K.W.; Zhou, S.; Vogelstein, B. A bacterial protein enhances the release and efficacy of liposomal cancer drugs. Science. 2006 Nov 24;314(5803):1308-1311.

Jiang, W.W.; Rosenbaum, E.; Mambo, E.; Zahurak, M.; Masayesva, B.; Carvalho, A.L.; Zhou, S.; Westra, W.H.; Alberg, A.J.; Sidransky, D.; Koch, W.; Califano, J.A. Decreased mitochondrial DNA content in posttreatment salivary rinses from head and neck cancer patients. Clin Cancer Res. 2006 Mar 1;12(5):1564-1569.

Masayesva, B.G.; Mambo, E.; Taylor, R.J.; Goloubeva, O.G.; Zhou, S.; Cohen, Y.; Minhas, K.; Koch, W.; Sciubba, J.; Alberg, A.J.; Sidransky, D.; Califano, J. Mitochondrial DNA content increase in response to cigarette smoking. Cancer Epidemiol Biomarkers Prev. 2006 Jan;15(1):19-24.

Sui, G.; Zhou, S.; Wang, J.; Canto, M.; Lee, E.E.; Eshleman, J.R.; Montgomery, E.A.; Sidransky, D.; Califano, J.A.; Maitra, A. Mitochondrial DNA mutations in preneoplastic lesions of the gastrointestinal tract: a biomarker for the early detection of cancer. Mol Cancer. 2006;5:73.

Zhou, S.; Kassauei, K.; Cutler, D.J.; Kennedy, G.C.; Sidransky, D.; Maitra, A.; Califano, J. An oligonucleotide microarray for high-throughput sequencing of the mitochondrial genome. J Mol Diagn. 2006 Sep;8(4):476-482.

Cheong, I.; Huang, X.; Thornton, K.; Diaz, L.A., Jr.; Zhou, S. Targeting cancer with bugs and liposomes: ready, aim, fire. Cancer Res. 2007 Oct 15;67(20):9605-9608.

Diaz, L.A., Jr.; Foss, C.A.; Thornton, K.; Nimmagadda, S.; Endres, C.J.; Uzuner, O.; Seyler, T.M.; Ulrich, S.D.; Conway, J.; Bettegowda, C.; Agrawal, N.; Cheong, I.; Zhang, X.; Ladenson, P.W.; Vogelstein, B.N.; Mont, M.A.; Zhou, S.; Kinzler, K.W.; Vogelstein, B.; Pomper, M.G. Imaging of musculoskeletal bacterial infections by [124I]FIAU-PET/CT. PLoS One. 2007;2(10):e1007.

Liu, C.; Zhou, S.; Begum, S.; Sidransky, D.; Westra, W.H.; Brock, M.; Califano, J.A. Increased expression and activity of repair genes TDP1 and XPF in non-small cell lung cancer. Lung Cancer. 2007 Mar;55(3):303-311.

Mithani, S.K.; Smith, I.M.; Zhou, S.; Gray, A.; Koch, W.M.; Maitra, A.; Califano, J.A. Mitochondrial resequencing arrays detect tumor-specific mutations in salivary rinses of patients with head and neck cancer. Clin Cancer Res. 2007 Dec 15;13(24):7335-7340.

Mithani, S.K.; Taube, J.M.; Zhou, S.; Smith, I.M.; Koch, W.M.; Westra, W.H.; Califano, J.A. Mitochondrial mutations are a late event in the progression of head and neck squamous cell cancer. Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4331-4335.

Zhou, S.; Kachhap, S.; Sun, W.; Wu, G.; Chuang, A.; Poeta, L.; Grumbine, L.; Mithani, S.K.; Chatterjee, A.; Koch, W.; Westra, W.H.; Maitra, A.; Glazer, C.; Carducci, M.; Sidransky, D.; McFate, T.; Verma, A.; Califano, J.A. Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7540-7545.

Chuang, A.Y.; Chuang, T.C.; Chang, S.; Zhou, S.; Begum, S.; Westra, W.H.; Ha, P.K.; Koch, W.M.; Califano, J.A. Presence of HPV DNA in convalescent salivary rinses is an adverse prognostic marker in head and neck squamous cell carcinoma. Oral Oncol. 2008 Oct;44(10):915-919.

Liu, J.W.; Nagpal, J.K.; Sun, W.; Lee, J.; Kim, M.S.; Ostrow, K.L.; Zhou, S.; Jeronimo, C.; Henrique, R.; Van Criekinge, W.; Moon, C.S.; Califano, J.A.; Trink, B.; Sidransky, D. ssDNA-binding protein 2 is frequently hypermethylated and suppresses cell growth in human prostate cancer. Clin Cancer Res. 2008 Jun 15;14(12):3754-3760.

McFate, T.; Mohyeldin, A.; Lu, H.; Thakar, J.; Henriques, J.; Halim, N.D.; Wu, H.; Schell, M.J.; Tsang, T.M.; Teahan, O.; Zhou, S.; Califano, J.A.; Jeoung, N.H.; Harris, R.A.; Verma, A. Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem. 2008 Aug 15;283(33):22700-22708.

Zhao, M.; Mydlarz, W.K.; Zhou, S.; Califano, J. Head and neck cancer cell lines are resistant to mitochondrial-depolarization-induced apoptosis. ORL J Otorhinolaryngol Relat Spec. 2008 May 16;70(4):257-263.

Cheong, I.; Zhou, S. Tumor-specific liposomal drug release mediated by liposomase. Methods Enzymol. 2009;465:251-265.

Li, M.; Chen, W.D.; Papadopoulos, N.; Goodman, S.N.; Bjerregaard, N.C.; Laurberg, S.; Levin, B.; Juhl, H.; Arber, N.; Moinova, H.; Durkee, K.; Schmidt, K.; He, Y.; Diehl, F.; Velculescu, V.E.; Zhou, S.; Diaz, L.A., Jr.; Kinzler, K.W.; Markowitz, S.D.; Vogelstein, B. Sensitive digital quantification of DNA methylation in clinical samples. Nat Biotechnol. 2009 Sep;27(9):858-863.

Yun, J.; Rago, C.; Cheong, I.; Pagliarini, R.; Angenendt, P.; Rajagopalan, H.; Schmidt, K.; Willson, J.K.; Markowitz, S.; Zhou, S.; Diaz, L.A., Jr.; Velculescu, V.E.; Lengauer, C.; Kinzler, K.W.; Vogelstein, B.; Papadopoulos, N. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009 Sep 18;325(5947):1555-1559.

Schmidt-Kittler, O.; Zhu, J.; Yang, J.; Liu, G.; Hendricks, W.; Lengauer, C.; Gabelli, S.B.; Kinzler, K.W.; Vogelstein, B.; Huso, D.L.; Zhou, S. PI3Kalpha Inhibitors That Inhibit Metastasis. Oncotarget. 2010 Sep 1;1(5):339-348.

 

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