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Hope for Glioblastoma: Resection and New Treatments: Page 2 of 2

Hope for Glioblastoma: Resection and New Treatments: Page 2 of 2

GENETIC TARGETS

Some of the underlying genetic abnormalities associated with GBM include overexpression of the epidermal growth factor receptor (EGFR) gene and its most common deletion mutant variant III (EGFRvIII).8 Tyrosine kinase inhibitors have been used to block the ligand-activated tyrosine kinase activity of EGFR. Some tumors have been found to respond to this genetic attack, according to Friedman.

EGFR kinase inhibitors alone or in combination with other agents such as rapamycin are expected to be beneficial in selected patients, explained Friedman. Only 10% to 20% of patients with GBM reportedly responded to EGFR kinase inhibitors, though.9 Loss of expression of tumor suppressor gene PTEN and its protein phenotype is thought to produce cellular resistance to EGFR kinase inhibitor therapy in GBM.

Reduced sensitivity to EGFR kinase inhibitors in patients with GBM, therefore, has been linked to tumor coexpression of EGFRvIII and PTEN.9 The identification of this genetic and phenotypic relationship is an important step in the development of a tumor-specific treatment for GBM, according to Friedman.

"Whether these GBM tumors are EGRFvIII-positive or PTEN wild type—the latter of which augurs a particularly good response to erlotinib [Tarceva]—or whether the tumor response is linked to other molecular profiles, we will begin to unravel the molecular subsets that will predict a better outcome," Friedman said. He added that "once patients with GBM are treated with multi-modality overlapping therapies, we will begin to see a desperately needed increase in the cure and survival rates."

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References

REFERENCES
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4. Persson AI, Fan Q, Phillips JJ, Weiss WA. Glioma. In: Gilman S, ed. Neurobiology of Disease. New York: Elsevier Academic Press; 2007:433-444.
5. Fine HA, Barker FG, Markert JM, Loeffler JS. Neoplasms of the central nervous system. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer Principles & Practice of Oncology. Vol 2. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:1834-1887.
6. DeAngelis LM. Brain tumors. N Engl J Med. 2001;344:114-123.
7. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352:987-996.
8. Friedman HS, Bigner DD. Glioblastoma multiforme and the epidermal growth factor receptor. N Engl J Med. 2005;353:1997-1999.
9. Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastoma to EGFR kinase inhibitors. N Engl J Med. 2005;353:2012-2024.
 
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