Discovery of Oncogenes in Giloma

As the first group to carry out genomic profiling in glioma, we discovered and reported in 1999 that insulin-like growth factor binding protein 2 (IGFBP2) is overexpressed in high-grade gliomas. Since then, we have made major breakthroughs in understanding how IGFBP2 contributes to cancer progression.

We for the first time used a mouse model to provide evidence that IGFBP2 is an oncogene and that IGFBP2 cooperates with Akt in development of glioma (Proc Natl Acad Sci USA (104:11736-41, 2007). In a follow-up Proc Natl Acad Sci USA paper (106:16675-9, 2009), we reported that IGFBP2 upregulation results from loss of INK4a. Continuing this work, we published another paper in Proc Natl Acad Sci USA (109:3475-80, 2012) demonstrating that IGFBP2 activates the integrin/integrin-linked kinase/NFkB pathway in vivo in our mouse model.

We began to investigate the role of nuclear IGFBP2 in gliomagenesis and discovered that IGFBP2 potentiate nuclear signaling function and transcriptional program mediated by nuclear EGFR-STAT3 (Oncogene 2015 Apr 20. doi: 10.1038/onc.2015.131). I believe that it is partially because of our work in the last 11 years that the importance of IGFBP2 in cancer is being increasingly recognized and that IGFBP2 and its pathway have emerged as a new therapeutic target.

In this application, we hope to continue this success and make further important contribution to the field focusing on IGFBP2.

My group was also one of the first few to use next-generation sequencing technology to characterize transcriptome and gene fusion. We discovered and characterized a novel gene fusion, FGFR3-TACC3, as a driver event for glioma.

This paper was recently published in Journal of Clinical Investigation (123:855-865, 2013), accompanied by a commentary. This fusion gene has since been found in multiple cancer types (e.g., bladder and lung) unlike most other fusion gene reported, suggesting its fundamental role in carcinogenesis that is not restricted by tissue specificity. We are continuing on functional investigation of this fusion gene.

Selected Research

Dunlap SM, Celestino J, Wang H, Jiang R, Holland E, Fuller GN, and Zhang W. Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad. Sci. USA 104(28):11736-41, 2007.

Moore L, Holmes K, Smith S, Wu Y, Tchougounova E, Uhrbom L, Sawaya R, Bruner JM, Fuller GN, Zhang W. IGFBP2 is a candidate biomarker for Ink4a-Arf status and a therapeutic target for high-grade gliomas. Proc Natl Acad Sci USA 106(39):16675-9, 2009.

Holmes KM, Annala M, Chua Y, Dunlap SM, Liu Y, Niek N, Cogdell D, Hu L, Hess K, Nykter M, Fuller GN, and Zhang W. IGFBP2-driven glioma progression is prevented by blocking a clinically significant network of integrin, ILK, and NFκB. Proc Natl Acad Sci USA 109(9):3475-80, 2012.

Turner K, Sun Y, Ji P, Granberg K, Bernard B, Hu L, Cogdell D, Zhou X, Yli-Harja O, Nykter M, Shmulevich I, Yung WKA, Fuller GN, Zhang W. Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression. Proc Natl Acad Sci USA 112(11):3421-6, 2015.