Suppression of human brain tumor with interference RNA specific for tenascin-C

Abstract

Glioblastoma multiforme (GBM) accounts for approximately 12-15% of intracranial neoplasms. The GBM remains refractory to therapy because of tumor heterogeneity, local invasion, and nonuniform vascular permeability to drugs. Patients with GBM have the median survival of approximately 8-10 months, and for those cases where tumor recurs, the average time of tumor progression after therapy is only 8 weeks. A combination of different treatment modes as surgery and chemo- or/and radiotherapy extend survival only for a short time, if any. Recently, tenascin-C (TN-C) as a dominant epitope in glioblastoma has been discovered. It is transiently expressed during organogenesis, absent or much reduced in most fully developed organs, but reappears under pathological conditions such as infection, inflammation, or tumorigenesis. It was found that the intensity of TN-C staining correlates with the tumor grade and that the strongest staining indicates poor prognosis. In this paper we selected 11 GMB patients with poor prognosis for an interference RNA treatment, which followed a brain resection. ATN-RNA, a double stranded RNA with nucleotide sequence homologous to tenascin-C mRNA, was administered directly into the 2-5 sites located in the area of neoplastic brain infiltration which can not be removed surgically. For the first time RNA interference technology was applied, to suppress human brain tumors (glioblastoma multiforme, astrocytoma) through inhibition of the synthesis of tenascin-C.