Research / Clinical Summary

Frank Furnari, PhD Associate Professor, Medicine Cancer Biology Program Contact by Email

My research interests involve investigating the genetic lesions of advanced stage gliomas. Specifically, the focus of my research group is on the most prevalent of these lesions; amplification and truncation of the epidermal growth factor receptor gene (DEGFR) and losses of heterozygosity for chromosome 10, for which the phosphatase and tensin (PTEN) homology gene, located at 10q23.3 is one target. Deciphering how mutations of these two genes alter their normal functions is an important step in understanding the transition from grade III glioma to glioblastoma.

Two approaches have been taken to define molecules that are regulated downstream of the truncated EGFR. First, gene products that control cell cycle progression were examined for alterations in their activities or expression levels. These studies showed that CDK2-Cyclin A activity, concomitant with RB protein hyperphosphorylation, was elevated in U87MG-DEGFR tumors, correlating with a decrease in expression of the cyclin-dependent kinase (CDK) inhibitor, p27. In addition, activated phosphatidylinositol 3-kinase (PI3-K) and phosphorylated Akt levels were also elevated in U87MG-DEGFR tumors. These effects were reversible upon treatment with the PI3-K inhibitor, LY294002, or expression of a kinase dead dominant negative Akt mutant, suggesting that DEGFR can enhance cell proliferation in part by down-regulation of p27 mediated through activation of the PI3-K/Akt pathway. Second, DEGFR-mediated changes in gene expression of intracranial tumors were assessed by DNA microarrays. The DEGFR-specific transcriptome defines new genes that may provide additional avenues for clinical intervention. For example, a number of genes specific for DEGFR signaling are STAT pathway responsive, such as IL-6 and Il-8. To this end we have confirmed that STAT3 is activated in both U87MG-DEGFR generated tumors and glioblastoma tumor samples expressing DEGFR and that U87MG-DEGFR cells secrete high levels of IL-6 and IL-8.

As an initial step in defining the role of PTEN in glioma progression we showed that expression of PTEN in PTEN-null glioma cell lines caused growth inhibition. Interestingly, similar expression in glioma cells with intact endogenous PTEN alleles had no inhibitory effects suggesting dosage control of PTEN effects and, perhaps, downstream mutations in other components of the pathway in such cells. To further understand the function of this phosphatase, PTEN-interacting proteins have been isolated by two-hybrid analysis. The role of these proteins in modulating the apoptotic process, cellular proliferation, invasion and migration and their potential as bone fide PTEN protein substrates is being explored.

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