Dr. Oliver Bogler
The University of Texas MD Anderson Cancer Center
Department of Neurosurgery
- Molecular and cellular biology of gliomas
- Signal transduction
- Adaptor proteins
- Receptor tyrosine kinase regulation
- Glial transformation
- Regulation of DNA methylation
- Response to chemotherapeutics; cancer genetics
There are two main areas of research being pursued in my laboratory:
Abnormal EGFR signaling in glioma - nuclear EGFR targets identified by mass spectrometry
Dysregulation of receptor tyrosine kinases is a major contributor to cancer, including glioblastoma, where amplification and mutation of epidermal growth factor receptor (EGFR) is often found. The most common mutation is in-frame deletion of exons 2-7, known as EGFRvIII, EGFR* or ΔEGFR. EGFRvIII confers enhanced tumorigenicity on glioma cells in vivo, reducing apoptosis and increasing proliferation. EGFRvIII signals constitutively and at approximately 5-to-10-fold lower intensity than wild-type.
We are investigating the pathways that are preferentially activated by EGFRvIII, using a phosphotyrosine-directed, mass spectrometry-based shotgun phosphoproteomics approach. A study of two different cell lines, LNZ308 (PTEN null) and LN428 (PTEN wt) identified 249 tyrosine phosphorylated proteins. Statistical analysis revealed several signals that were prevalent in EGFRvIII expressing glioma cells, including phosphorylation of STAT5, Gab1 and MIG6.
Identification of STAT5 as a target of EGFRvIII prompted an investigation of whether EGFRvIII is active in the nucleus. We have identified EGFRvIII associated with phosphorylated STAT5 on chromatin, and capable of activating the expression of STAT5 target genes, including Aurora A kinase, which positively regulate glioblastoma malignancy. STAT5 promotes expression of the EGFRvIII target gene Bcl-XL, and knockdown of STAT5 reduces the transformation induced by EGFRvIII. Furthermore, we have mutated signals in EGFRvIII that regulate nuclear localization, and are examining the impact of these on its ability to promote tumor growth.
In a related study we have used artificial receptor dimerization, mediated by technology from Ariad Pharmaceuticals, to enhance the EGFRvIII signal. A chimeric version of EGFRvIII was created, in which the receptor was fused N-terminally with two FKBP-F36V domains that could be activated by the chemical inducer of dimerization, AP20187. This has resulted in a more oncogenic form of EGFRvIII that emits a stronger signal, and we are using this to deepen our phosphoproteomics analysis to seek additional preferential targets of EGFRvIII action.
The ultimate goal of this work is to identify new targets for therapy development, which can be used in combination with existing therapies, to gain control of high grade gliomas.
Analysis of the clinical potential of a new generation of platinum compounds and assessing the role of p53 in mediating response
We are interested in a new generation of multinuclear platinum compounds, the BBR series, which show greater efficacy and lower toxicity than cisplatin. These compounds have been developed by Dr. Nick Farrell (VCU, Richmond, VA), a chemist developing novel platinum compounds. Clonogenic assays in culture and analysis of xenografts in mice have shown that BBR compounds are more potent than cisplatin in the killing of glioma cells. At concentrations that kill 90% of the cells in culture the BBR compounds effectively induce components of the MAPK signaling pathway. Recently we have performed a comprehensive analysis of the cellular response to BBR3610, and found that a period of G2/M arrest and autophagy is followed by apoptosis, and that the few cells that escape death enter senescence that is accompanied by mitotic catastrophe. Ongoing efforts focus on using genomics and proteomics to understand the differences in the cellular response to these drugs, and to generate profiles that may predict response.
Office: MDA FCT6.5012 (Unit 1422)
Ph.D. - Ludwig Institute for Cancer Research - 1991