Second messenger systems in human gliomas

Patients with glioblastoma (astrocytoma, World Health Organization grade IV) exhibit 2-year survival rates of less than 20% despite significant advances in therapeutic options available to patients. Epidermal growth factor receptor (EGFR) hyperexpression is one of the most commonly encountered abnormalities in this tumor. However, EGFR expression, amplification, and mutations are poorly predictive of patient survival. Investigators have taken to exploiting the sensitivities of activated downstream targets in the EGFR second messenger pathways to certain inhibitory drugs to downregulate their neoplastic messages promoting cell growth and inhibiting cell death.

It is important to both gain some understanding of the functional significance of these pathways and to understand the role the pathologist might play in characterizing the activation status of certain downstream messenger proteins that are targeted in these brain tumor therapies. We have reviewed the literature regarding histologic assays that have been incorporated into trials of these new drugs and report on the methods used to study these proteins and the conclusions of these studies.

Literature review and primary material from Duke University (Durham, NC) Department of Pathology archives.

To date, drug trial reports indicate that identification of the presence of the EGFR variant, EGFRvIII, and measurement of the activated downstream targets, phospho-Akt, phospho-S6, and phospho-MAPK, may be useful in predicting sensitivity to some of the EGFR kinase inhibitors. No studies to date have identified prognostic significance related to immunoreactivity status among any of these markers that is independent of histologic grade.