Tailoring Treatment for Glioblastoma Multiforme
Abstract & Commentary
By Adilia Hormiga, MD, PhD, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical Center at Memorial Sloan-Kettering Cancer Center. Dr. Hormiga reports no financial relationship relevant to this field of study.
Synopsis: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.
Source: Mellinghoff IK, et al. Molecular Determinants of the Response of Glioblastomas to EGFR Kinase Inhibitors. N Engl J Med. 2005;353:2012-2024. Erratum in: N Engl J Med. 2006;354:884.
In recent years, new biologic agents such as inhibitors of the kinase domain of epidermal growth factor receptor (EGFR) have been used in phase I and phase II clinical trials for patients with recurrent glioblastoma multiforme (GBM). Erlotinib and Gefitinib belong to this class of agents. In GBM tumors EGFR can be overexpressed, amplified, or mutated to be independent of ligand for activation. When the epidermal growth factor ligand binds the EGFR, it initiates signal transduction through PI3K/AKT pathway. A normal inhibitor of this pathway is the tumor suppressor protein, PTEN. In some GBM, PTEN can be lost. In tumor cells, the loss of PTEN together with constitutive activation of the receptor promotes deregulation of the PI3K/AKT signaling pathway, leading to proliferation and inhibition of cell death.
Mellinghoff and colleagues sequenced the kinase domain of EGFR and EGFR type 2 (Her 2/neu) and analyzed the expression of EGFR, EGFRvIII (constitutively active genomic deletion variant of EGFR), and PTEN protein in tumor tissue of high-grade glioma patients who were treated either with Erlotinib or Gefitinib. They did not find mutations of the kinase domain of the receptors in tumor specimens from 26 patients. EGFR was amplified in 12 of 25 GBMs but no association was found between amplification and response to treatment with EGFR kinase inhibitors. EGFRvIII was detected in 12 of the 26 patients, and 6 of those 12 patients had a response to EGFR inhibitors. In 7 of 13 patients, PTEN protein was present in their tumors and correlated with response to treatment, while all tumors with PTEN loss did not respond to EGFR inhibitors. They verified their data by analyzing tissue from 33 other patients from a different institution. Eight of the 33 patients had a clinical response associated with the coexpression of EGFRvIII and PTEN. They supported their findings from tumor tissue analysis with in vitro studies showing that coexpression of EGFRvIII and PTEN in U87MG glioblastoma cells in tissue culture sensitized the tumor cells to Erlotinib.
GBM is the most frequent brain tumor in adults and is almost invariably fatal in about one year. Although chemotherapy with alkylating agents has been used to treat GBM in the United States, only recently was shown definitely that temozolomide chemotherapy during the course of radiation followed by adjuvant temozolomide improved survival of patients when compared to those who received radiotherapy alone.1 Patients receiving temozolomide in that study responded to treatment and had a longer survival when methylation of promoter for MGMT (O6-methylguanine-DNA methyltransferase DNA-repair gene) was found in their tumor tissue.2 Their work showed that response to treatment and prognosis could be correlated to an epigenetic variation.
What Mellinghoff et al's paper taught us was that GBM response to EGFR inhibitors was associated with coexpression of both EGFRvIII and PTEN. Although their results will need further validation, and upfront treatment is not yet based on the molecular features of a particular tumor. Last year's publications, listed below, may establish a new era for GBM management. Identification of molecular events may allow a more rational treatment approach in the future by using a single or combination of agents the target that specific molecular event(s) or pathways that drive tumor maintenance in an individual patient.
1. Stupp R, et al. Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med. 2005;352:987-996.
2. Hegi ME, et al. MGMT Gene Silencing and Benefit From Temozolomide in Glioblastoma. N Engl J Med. 2005;352:997-1003.