Antisense Oligonucleotides Therapy: A New Potential Tool in the Treatment of Cerebral Gliomas

Pp. 69-115 (47)

Gerardo Caruso, Maria Caffo, Maria Angela Pino and Giuseppe Raudino

Abstract

Gliomas account for about 45% of all primary central nervous system tumors and 77% of all malignant primary cerebral tumors. Recent studies in molecular biology have better depicted the mechanisms involved in the genesis of cerebral gliomas. It is now generally understood that tumor genesis occurs either by over-expression of oncogenes or inactivation of tumor suppressor genes. The two main gene groups involved in brain tumor development are proto-oncogenes and tumor suppressor genes, respectively up-regulated and downregulated during the tumor initiation and progression. It's evident that the modulation of gene expression at more levels, such as DNA, mRNA, proteins and transduction signal pathways, may be the most effective modality to downregulate or silence specific genic functions. Nowadays, an efficacious strategy in the gliomas treatment does not yet exist. In series of patients affected by malignant gliomas mortality is still close to 100% and the survival rate in glioblastoma multiforme patients is less than 1 year.

A potential and future therapeutic approach in gliomas treatment is represented by antisense therapy targeting different antigens or signal pathway of growth factors and their receptors like IGF-I, TGF-beta2 or EGF. The antisense strategy is based on use of antisense oligonucleotides (gene therapy sensu strictu) or of antisense expressing vectors (cell gene therapy). The clinical results obtained using antisense therapy are often similar than those obtained by use of certain inhibitors (i.e. imatinib, getifinib) including antibodies (avastin) targeting the growth factors and their downstream element of signaling pathways. The results are especially interesting if applying the combined techniques of antisense and/or inhibitors with chemotherapy. Using either the approach of inhibitors of growth factors and their receptors, especially of EGF, or the approach of antisense IGF-I and anti TGF-beta inducing anti-tumor response, the median survival of glioblastoma patients can reach currently two years if combined with chemotherapy (temozolomide). These results constitute a progress as compared to classical treatment and underline the value of molecular biology based gene therapy, especially immune-gene therapy.

In this chapter we describe the most relevant findings of antisense oligonucleotides application in gliomas treatment pointing out the attention on effectiveness, delivery system possibilities, targeting modalities and safety of this therapeutic strategy.

Keywords:

Antisense Oligonucleotides Therapy, Gene Therapy, Glioblastoma Multiforme, Gliomas.

Affiliation:

Neurosurgical Clinic, Department of Neuroscience, A.O.U. Policlinico “G. Martino”, via Consolare Valeria, 1, 98125 Messina, Italy.