Summary of Research ProgramsWei Zhang, Ph.D.
Department of Pathology
The University of Texas M. D. Anderson Cancer Center
Published Scientific Accomplishments
Functional characterization of IGFBP2/IIp45 in cancer invasion
Dr. Zhang identified the first temperature-sensitive mutant of human p53 (EMBO J 13:2535-2544, 1994); illustrated the importance of functional analysis of p53 mutants found in human tumors by demonstrating that some p53 mutants only partially lose the DNA binding and transactivation functions (Oncogene 8:2555-2559, 1993; Cancer Res. 83:4772-4775, 1993); discovered that phosphorylation of p53 modulate the functions of p53 (Cancer Res. 54:4448-4453, 1994; Cell Death & Differentiation, 5:584-591, 1998); and identified that cell death promoting gene Fas/APO-1 and oncogene H-ras are transcriptionally regulated by p53 (Mol Cell Biol. 15:3032-3040, 1995; Int. J. Oncol 7:1021-1028, 1995). He received NIH funding to further study the role of phosphorylation in functional regulation of p53, especially in response to radiation and chemotherapy treatment. He provided the first evidence that links the cell cycle regulator p21/WAF1/Cip1 to chemoresistance (Clin Cancer Res. 1:1051-1057, 1995), de-linked p21/WAF1/Cip1 from apoptosis promotion (Oncogene 11:2311-2316, 1995), identified p53-independent pathway for p21/WAF1/Cip1 activation (Cancer Res. 55:668-674, 1995; Cell Growth & Differentiation 6:909-913, 1995; Cancer Res. 57:3929-3934, 1997), and found that p21/WAF1/Cip1 is overexpressed in gliomas and brain metastases (Oncogene 11:2021-2028, 1995; J. Neuro-Oncol, 37:223-228, 1998). Using a tetracycline-inducible system, he discovered that overexpressed p21/WAF1/Cip1 confers glioma cells resistance to BCNU and cisplatin (Cancer Res. 58:1538-1543, 1998). Using antisense approach, his group found that downregulation of p21/WAF1/Cip1 sensitized glioma cells to BCNU and cisplatin (Clinical Cancer Res. 5:197-202, 1999).
In collaboration with Drs. Fuller and others, Dr. Zhang has been working on a glioma gene expression profiling program for the past five years (J. Genetic Medicine 1:57-59, 1997; Oncol. Rep. 6:393-401, 1999Oncogene 18:2711-2717, 1999; Cancer Res. 59:4228-4332, 1999). Drs. Fuller and Zhang first discovered that Insulin-like growth factor binding protein 2 (IGFBP2) is overexpressed in the most advanced stage of gliomas. Recently in a PNAS paper (Dunlap et al., 2007), we demonstrated that IGFBP2 is an oncogene for glioma. Dr. Zhang, together with his colleagues, Drs. Fuller and Holland, received two ARP/ATP grants from Texas Higher Education Board to work on two glioma functional genomics projects and published a number of papers from these work. Drs. Zhang and Fuller have received an RO1 to continue the glioma genomics and animal model studies. The current glioma genomic project is supported by Bullock Brain Tumor Research Fund to Drs. Sawaya, Zhang, and Fuller. In collaboration with Dr. Pollock and others, Dr. Zhang has been working on a leiomyosarcoma genomics project and is awarded an 4-year RO1 from NCI/NIH. A recent PNAS paper (Price et al., 2007) reported our finding of a robust gene pair that distinguishes GIST from LMS. In collaboration with Dr. Shmulevich, Dr. Zhang is actively participating in research of genetic regulatory network and published a series of papers on this topic. An R21 grant was funded with Dr. Shmulevich as the PI and Dr. Zhang as the co-PI. An RO1 by Drs. Shmulevich and Zhang was funded by the end of 2004. These fundings will greatly enhance our research in systems biology. Dr. Zhang's funding also include a pilot project in the EXPORT grant directed by Dr. Jones and CCSG grant that supports the genomics core.
Drs. Zhang and Shmulevich published a book entitled Computational and Statistical Approaches to Genomics in 2002 and the second edition was published in 2006. Drs. Zhang and Fuller have a book entitled "Genomic and Molecular Neuro-Oncology" published in November 2003 and this book was translated into Chinese in 2005. Drs Zhang, Shmulevich, and Astola published a book entitled "Microarray Quality Control" in 2004.
His former graduate student James Jabbur received an American Legion Fellowship, an AACR-AFLAC Scholar in Cancer Research award to present his recent work on p53 in 1999 AACR annual meeting, third prize at 2000 graduate student research competition, and the first prize (poster) at 2001 MDACC Trainee Recognition Day event. James published his thesis work in two papers in Oncogene, one paper each in Cancer Biology and Therapy and the Journal of Molecular Medicine. James graduated in 2001. Former graduate student Yu Yang won the first prize (Master degree group) in the annual graduate student research poster competition of GSBS in 1997 and graduated with a Master degree in 1999. Former graduate student Hua Wang has identified the function of IGFBP2 as an invasion enhancer gene, a paper to be published in Cancer Research as an Advances in Brief in August, 2003. Hua received the third prize in 2001 graduate student research competition, a Travel Award from graduate school to present a poster at USCAP conference in 2003, and the first prize [poster] at 2003 MDACC Trainee Recognition Day event. Hua has graduated with a PhD in August 2003. Hua recently received a fellowship from DOD and worked at the Breast Cancer Center at Baylor College of Medicine for a second postdoc training before returning to MDACC as a Research Scientist. Former graduate student Matt McDonald presented his work at Society of Neuro-Oncology meeting and at 2003 AACR symposium. Matt successfully defended his PhD thesis in August 2004.
The current graduate student Sarah Dunlap received a NIH training grant. Sarah presented her work in three national conferences in 2005-2006. She received a AACR Scholar-in-Training award to attend the AACR meeting. Sarah received the second prize in Basic Science platform presentation category in 2006 MDACC Trainee Recognition Day. In the 2007 Trainee Recognition event, Sarah won the first place in the category of Translational Research and gave a platform presentation. Sarah is also recipient of American Legion Fellowship. Graduate student. Sarah's work has recently been published in PNAS. Jheri Dupart successfully competed for a 3 year NIH predoctoral training grant. Jheri received an AACR-NCI-EORTC Minority Scholar Award to present at the International conference on Molecular Targets and Cancer therapeutics in Philadelphia, November 14-18, 2005. Jheri also received the Minority Faculty Association (MFA) Scholarship: Jones/Wharton Cancer Research Scholarship, Texas Medical Center, 2006. The MD/PhD program student George Wang has completed his PhD/MD training and will go to Mt Sinai for his medical internship. His work was published in a JBC paper. Recently, a new graduate student Kristen Holmes has joined the lab for her PhD thesis.
Press release on Sarah's PNAS paper
M. D. Anderson Team Identifies New Oncogene for Brain Tumors M. D. Anderson News Release 07/02/07
An overexpressed gene found at the scene of a variety of tumors is implicated in the development of two types of malignant brain cancer in a paper by researchers at The University of Texas M. D. Anderson Cancer Center to be published in the Proceedings of the National Academy of Sciences. The paper will be posted online at the PNAS web site the week of July 2. "Just because a gene is associated with cancer doesn't mean that it's actually causing cancer. In this paper we show for the first time that insulin-like growth factor binding protein 2 (IGFBP2) connects with two other proteins to fuel development and progression of brain tumors," says senior author Wei Zhang, Ph.D., professor in M. D. Anderson's Department of Pathology. Using a gene transfer delivery system in a mouse model, a team led by Zhang and Professor of Pathology Gregory Fuller, M.D., Ph.D., shows that IGFBP2 plays an active role in the tumorigenesis of astrocytoma and oligodendroglioma. Both cancers are forms of glioma, cancers that develop in the glial cells - which normally support and nourish neurons - that are highly resistant to treatment. "This makes IGFBP2 an important candidate for development of targeted therapy to treat gliomas," Zhang says. Gliomas kill about 13,000 people in the United States annually. The possibilities are not limited to brain cancer, Fuller notes, "because of the pervasive overexpression of IGFBP2 documented in other cancer types." The gene is expressed only at low levels in normal cells, which would potentially reduce side effects caused by a treatment that targeted the gene or its protein product. Fuller and Zhang first associated overexpression of the gene with brain cancer in 1999. Other researchers have since found it to be overexpressed in prostate, ovarian, breast and colorectal cancers, some leukemias, and also in drug-resistant tumors. Overabundance of IGFBP2 has since been shown to be an indicator of poor prognosis for glioma patients. The PNAS paper takes it beyond this biomarker status. Zhang, Fuller and colleagues employed a viral gene transfer delivery agent known as RCAS, which is loaded with the gene, or genes, of interest and injected into the mouse brain. The viral particles infect only glial cells, where the genes are expressed. This system allows the researchers to observe whether a gene identified in a correlation study plays an active role in tumorigenesis. It also permits the delivery and study of combinations of genes. They found that a combination of IGFBP2 and another known oncogene called K-Ras leads to development of astrocytomas - a glioma named for the star-like shape of its constituent cells. A combination of K-Ras and a third gene, Akt, previously had been shown to develop astrocytomas. Activation of Akt fuels cell growth and survival. None of the three genes caused brain cancer formation when delivered alone. The researchers tried a combination of Akt and IGFBP2 and no tumor formed, suggesting that the two genes lie in the same molecular pathway and have a similar effect. For oligodendroglioma, the researchers found that IGFBP2 combined with platelet-derived growth factor beta (PDGFB) results in a higher-grade form of the cancer than that caused by PDGFB alone. The high-grade tumors formed by the combination were indistinguishable in their shape and brain-invasive behavior from human oligodendrogliomas. The combination also activated the Akt pathway, which PDGFB does not induce by itself. Combined with their earlier findings, this led the team to hypothesize that IGFBP2 activates the Akt pathway, which they confirmed in subsequent lab experiments. In a final experiment, they treated IGFBP2-PDGFB infected cells in culture with a known Akt inhibitor, which killed more of the combination cells than those infected only with platelet-derived growth factor. This connection to Akt, the researchers note, makes the presence of IGFBP2 in blood serum a potential biomarker that would indicate an active role for Akt in a patient's cancer and thus a role for Akt inhibitors in their treatment. "The survival of the most advanced stage of glioma, gliobastoma, has not significantly improved for decades," note Zhang and Fuller. "We hope IGFBP2 will provide an effective target for treatment of this devastating disease." Sarah Dunlap, a student in the Graduate School of Biomedical Sciences jointly operated by M. D. Anderson and The University of Texas Health Science Center at Houston, is the report's first author. Other Fuller and Zhang team members include Joseph Celestino, department of gynecological oncology and Hua Wang, department of gastrointestinal oncology, both of M. D. Anderson; Rongcai Jiang, of Tianjin Medical University; and Eric Holland, of the Memorial Sloan-Kettering Cancer Center Department of Neurosurgery. Research was funded by the National Cancer Institute of the National Institutes of Health, and Dunlap's fellowship by the Keck Center Pharmacoinformatics Training Program of the Gulf Coast Consortia and the American Legion Auxiliary of Texas. 07/02/07