IGF-I: from diagnostic to triple-helix gene therapy of solid tumors.

Abstract

Alterations in the expression of growth factors and their receptors are associated with the growth and development of human tumors. One such growth factor is IGF-I (insulin-like growth factor I ), a 70-amino-acid polypeptide expressed in many tissues, including brain. IGF-I is also expressed at high levels in some nervous system-derived tumors, especially in glioblastoma. When using IGF-I as a diagnostic marker, 17 different tumors are considered as expressing the IGF-I gene. Malignant glioma, the most common human brain cancer, is usually fatal. Average survival is less than one year. Our strategy of gene therapy for the treatment of gliomas and other solid tumors is based on: 1) diagnostic using IGF-I gene expression as a differential marker, and 2) application of "triple-helix anti-IGF-I" therapy. In the latter approach, tumor cells are transfected with a vector, which encodes an oligoribonucleotide--an RNA strand containing oligopurine sequence which might be capable of forming a triple helix with an oligopurine and/or oligopyrimidine sequence of the promotor of IGF-I gene (RNA-IGF-I DNA triple helix). Human tumor cells transfected in vitro become down-regulated in the production of IGF-I and present immunogenic (MHC-I and B7 expression) and apoptotic characteristics. Similar results were obtained when IGF-I antisense strategy was applied. In both strategies the transfected cells reimplanted in vivo lose tumorigenicity and elicit tumor specific immunity which leads to elimination of established tumors.

Glioma Cells With Genetically Engineered IGF-I Receptor Downregulation Can Persist in the Brain in a Dormant State

“…The critical role that the IGF axis plays in the growth of GBM has been well documented in various experimental models (6,22,23). In early studies, the IGFs were shown to enhance 3D growth of glioblastoma (21) and more recently, high IGF-IR expression levels were identified as an independent prognostic factor associated with shorter survival, a poorer response to temozolomide (4) and resistance to anti-EGFR (24) and anti-PDGFR (25) treatments in GBM patients.…”

“…Thus, C6 cells may have become apoptotic if their IGF-IR expression levels were below the threshold required for survival, or entered cell cycle arrest if they expressed the requisite receptor levels for survival but not for cell cycle entry. A variable response of the tumor microenvironment to tumor cells with different IGF-IR expression levels may also have contributed to the divergent outcomes, as IGF-IR signaling levels were shown to affect tumor cell immunogenicity (23,34).…”

Immunotherapy of Malignant Tumors Using Antisense Anti-IGF-I Approach: Case of Glioblastoma

“…We suggest that anti-gene cell therapy, giving comparable results to those of currently applied chemotherapy, inhibitors or antibodies [72] [73] [85], could be used either alone [57] [86] or as combined therapies i.e. antisense targeting simultaneously different elements of growth factors signalling pathway [49] [91], including study of control CD8 (+) T-cell effect or functions [92], new tools of cell transfection [93] and especially the search for new onco-proteins [94] and growth factor targets [14] [50] [65] [95] [96] appear as the near future challenge. Among growth factors, targeting IGF-I system in relation with cancer therapy constitutes ongoing basic and clinical research [97]- [99]; the IGF-I being considered as one of the principal precancerous markers [3] [100] [101], has conducted to experiments on suppression of IGF-I expression in tumors, following directly by immuno-gene therapy of malignant tumors.…”

Advances in Experimental and Translational Research in the Treatment of Hepatocellular Carcinoma

“…Such antisense technology is being developed to target the growing list of oncogenes and local growth factors that have been identified in the development of HCC [19,24]. Targets being that have been examined include the FGF-2, IGF-I, VEGF-2, and COX-2 genes [29][30][31]. Use of these techniques has shown antitumor effects in vitro and in animal models.…”