Growth factor receptors as therapeutic targets: strategies to inhibit the insulin-like growth factor I receptor

被引:122
作者
Surmacz, E [1 ]
机构
[1] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
关键词
insulin-like growth factor receptor; anti-cancer drugs; antibodies; tyrosine kinase inhibitors; antisense; triple helix; dominant-negative mutants;
D O I
10.1038/sj.onc.1206772
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neoplastic transformation is often related to abnormal activation of growth factor receptors and their signaling pathways. The concept of targeting specific tumorigenic receptors and/or signaling molecules has been validated by the development and successful clinical application of drugs acting against the epidermal growth factor receptor 2 (HER2/neu, Erb2), the epidermal growth factor receptor 1 ( EGFR, HER1), the Brc-Abl kinase, the platelet-derived growth factor receptor, and c-kit. This review will focus on the next promising therapeutic target, the insulin-like growth factor I receptor ( IGF-IR). IGF-IR has been implicated in a number of neoplastic diseases, including several common carcinomas. From a pharmaceutical standpoint, of particular importance is that IGF-IR appears to be required for many transforming agents ( genetic, viral, chemical) to act, but is not obligatory for the function of normal adult cells. The tumorigenic potential of IGF-IR is mediated through its antiapoptotic and transforming signaling, and in some cases through induction of prometastatic pathways. Preclinical studies demonstrated that downregulation of IGF-IR reversed the neoplastic phenotype and sensitized cells to antitumor treatments. 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 mutants, and various compounds reducing ligand availability. The experience with these strategies combined with the knowledge gained with current anti-growth factor receptor drugs should streamline the development of anti-IGF-IR therapeutics.
引用
收藏
页码:6589 / 6597
页数:9
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