Insulin like growth factor-1 receptor: An anticancer target waiting for hit

Abstract

The Insulin like Growth Factor-1 (IGF-1) receptors are members of the super family of Receptor Tyrosine Kinase (RTKs) implicated in human cancers due to amplification, overexpression or somatic mutation of the gene. The type-1 insulin like growth receptors (IGF-IR) is overexpressed by many tumors and mediates proliferation, motility and apoptosis protection. Tumor growth and metastasis can be blocked by agents that inhibit IGF-IR expression or function, suggesting that the IGF-IR is a promising treatment target. The strategies to block IGF-IR function employed anti-IGF-IR antibodies, small-molecule inhibitors of the IGF-IR tyrosine kinase, antisense oligodeoxynucleotides and antisense RNA, small inhibitory RNA, triple helix, dominant negative mutant and various compounds reducing ligand availability. Studies show that antisense IGF-IR expression in melanoma cells leads to enhanced radio sensitivity and impaired activation of ATM, required for DNA double strand break repair. Antisense and dominant negative strategies also enhance tumor cell chemosensitivity induced by tumor cells and killed in vivo by IGF-IR antisense. However, antisense agents cause only modest IGF-IR down regulation and can affect the insulin receptor. Specificity is an important issue for the development of both kinase inhibitors and molecular reagents. Using an array-based screen to identify accessible region of IGF-IR mRNA, are designed small interfering RNAs (siRNAs) that induce potent IGF-IR gene silencing without affecting the insulin receptor. These siRNAs block IGF-signaling, enhancing radio and chemosensitivity and show a genuine therapeutic potential. The clinical efficacy of IGF-IR targeting will be determined by key factors including the role of receptors in established tumors. The potency of inhibition achieved in vivo and the extent to which other signaling pathways compensate for IGF-IR loss. © 2007 Academic Journals.