Inhibition of insulin-like growth factor receptor-1 as promising anticancer therapeutic

Scientists report that an unlikely molecule has emerged as an attractive target for development of therapeutics aimed at a diverse spectrum of tumors, including some malignancies that are resistant to conventional therapies. Two studies published online in Cancer Cell demonstrate that the insulin-like growth factor 1 receptor (IGF-1R) is required for the survival of tumor cells and provide direct evidence that inhibition of IGF-R1 using selective small molecules represents a novel potential anticancer treatment.

Extensive studies have suggested that IGF-1R plays a role in the development of human cancers. IGF-1R is present in a broad range of tumor types including multiple myeloma, lymphoma, leukemia, and breast, lung, prostate, and colon cancers. However, IGF-1R has not been viewed as a likely target for cancer therapeutics because many normal cells also contain the protein. Research scientists from Dana-Farber Cancer Institute in Boston and Novartis Institutes for Biomedical Research Basel demonstrate that IGF-1R inhibition using a variety of methods had potent antitumor effects against many types of cancer cells grown in the laboratory, including cells that are resistant to conventional cancer therapeutics.

Molecular analyses demonstrated that IGF-1R inhibition impacts multiple intracellular signals related to cell proliferation or tumor development and provides possible mechanisms to explain how IGF-1R inhibition can make tumor cells more sensitive to conventional chemotherapy or other anticancer agents. Perhaps most significantly, IGF-1R suppresses tumor growth, prolongs survival, and enhances the antitumor effect of chemotherapy in clinically relevant mouse models of multiple myeloma and other hematological malignancies. The researchers also identify two small molecules that are selective inhibitors of IGF-1R and are active anticancer agents against tumors that contain IGF-1R. These small molecules represent highly attractive potential therapeutics.

According to study author Dr. Constantine S. Mitsiades of Dana-Farber, “These results suggest that IGF-1R function is critically required for tumor cell survival, but dispensable for survival of normal cells in adult animals. The preclinical activity of IGF-1R inhibitors against a broad spectrum of tumor cells and, importantly, their ability to sensitize tumor cells to a wide range of anticancer agents, highlight the major role of IGF-1R signaling for human malignant cells, and suggest that the molecular pathway of IGF-1R is an attractive potential target for development of anticancer therapeutics.”

Constantine S. Mitsiades, Nicholas S. Mitsiades, Ciaran J. McMullan, Vassiliki Poulaki, Reshma Shringarpure, Masaharu Akiyama, Teru Hideshima, Dharminder Chauhan, Marie Joseph, Towia A. Libermann, Carlos Garcia-Echeverria, Mark A. Pearson, Francesco Hofmann, Kenneth C. Anderson Andrew L. Kung: “Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies and solid tumors”

Carlos García-Echeverría, Mark A. Pearson, Andreas Marti, Thomas Meyer, Juergen Mestan, Johann Zimmermann, Jiaping Gao, Josef Brueggen, Hans-Georg Capraro, Robert Cozens, Dean B. Evans, Doriano Fabbro, Pascal Furet, Diana Graus Porta, Janis Liebetanz, Georg Martiny-Baron, Stephan Ruetz, Francesco Hofmann: “In vivo anti-tumour activity of NVP-AEW541 – A novel, potent and selective inhibitor of the IGF-IR kinase”

Published online 26 February 2004; Cancer Cell, Volume 5, Number 3, March 2004.