Interfering the EGFR activity — new options of therapy for patients with glial neoplasms?

Abstract

Glial neoplasms (mainly — astrocytomas GIV acc. to WHO classification) are the most often diagnosed malignant brain tumors in adults. EGFR amplification or overexpression of the protein is observed in 40–60% of glioblastoma multiforme, while such abnormalities are rarely detected in glial neoplasms of lower degree of malignancy. In approx. 40% of cases of glial tumors with EGFR amplification, EGFR mutation variant III (EGFRvIII) is also detected. EGFRvIII is usually coexpressed with wild type EGFR. EGFRvIII is more oncogenic than EGFR. One of the main methods of treatment of glioblastoma multiforme patients is radiotherapy, which leads to DNA damage. EGFR activity exerts an important role in DNA repair (particularly in double strand breaks — DSBs), which results in radioresistance. Administration of antibodies directed to EGFR or tyrosine kinase inhibitors leads to increased radiosensitivity. Erlotinib (inhibiting the activity of both EGFR and EGFRvIII) as well as gefitinib (counteracting exclusively EGFR activity) are the most often tested novel, EGFR-directed options of targeted therapy in patients suffering from glioblastoma multiforme. Despite encouraging data obtained from phase I studies, results of phase II studies are not so optimistic. In turn, monoclonal antibodies directed to EGFR and/or EGFRvIII (eg. cetuximab, nimotuzumab) are characterized by large molecular weight, therefore their administration in glial neoplasm patients may be ineffective due to blood-brain barrier. Preclinical studies testing antisense RNA, ribozimes and RNA interference are ongoing. Future experimental directions should focus on better understanding of genetic signature of different types of glial neoplasms as well as possibilities of combining molecularly directed therapy with conventional anticancer treatment.
Onkol. Prak. Klin. 2011; 7, 4: 215–223