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 non-uniform 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 eight 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.

Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization

“…Encouragingly, initial research using glioma cell lines showed that inhibition of TN-C using antibodies resulting in decreased proliferation and migration (143). As a result, one of the first studies of RNAi in humans was a study that injected dsRNA targeting TN-C into the brains of patients with recurrent gliomas (144). After positive results in the initial, 8 person, study, a larger 46 person trial was conducted (145).…”

Tenascin-C: Exploitation and collateral damage in cancer management

“…Although the use of antagomirs is still technically demanding and poses many difficulties, tenascin-C expression was successfully targeted with ATN-RNA (anti-tenascin-C-RNA), a double stranded RNA homologous to tenascin-C mRNA triggering its degradation. This approach was first tested in a few patients 21,22 and then extended to 46 patients with grade II, III and IV glioma where ATN-RNA had been injected into the area of neoplastic infiltration upon surgical resection of the primary or recurrent tumors. 23 Patient outcome was assessed as overall survival (OS) and quality of life (Karnofsky Performance Scale) in comparison to 48 patients that had obtained only brachytherapy.…”

Delivery of small-interfering RNA (siRNA) to the brain

“…As a result, most current preclinical strategies, and the single clinical study reported thus far [11], which have utilized siRNA for CNS diseases have relied on invasive introduction of siRNA into the target tissue within the brain via surgical penetration of the BBB. Among these, application of siRNA in its ‘naked’ form, or sequestered within liposomes (to enhance internalization by the target cells) have been tested in vivo in both animal studies and in a single clinical trial [11-15].…”