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.

Abstract

Insulin-like growth factors and their receptor (IGF-1R) have been implicated in cancer pathophysiology. We demonstrate that IGF-1R is universally expressed in various hematologic (multiple myeloma, lymphoma, leukemia) and solid tumor (breast, prostate, lung, colon, thyroid, renal, adrenal cancer, retinoblastoma, and sarcoma) cells. Specific IGF-1R inhibition with neutralizing antibody, antagonistic peptide, or the selective kinase inhibitor NVP-ADW742 has in vitro activity against diverse tumor cell types (particularly multiple myeloma), even those resistant to conventional therapies, and triggers pleiotropic antiproliferative/proapoptotic molecular sequelae, delineated by global transcriptional and proteomic profiling. NVP-ADW742 monotherapy or its combination with cytotoxic chemotherapy had significant antitumor activity in an orthotopic xenograft MM model, providing in vivo proof of principle for therapeutic use of selective IGF-1R inhibitors in cancer.

• Authors: 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 García-Echeverría, Mark A Pearson, Francesco Hofmann, Kenneth C Anderson, Andrew L Kung
• Journal: Cancer cell (Cancer Cell) Vol. 5 Issue 3 Pg. 221-30 (Mar 2004) ISSN: 1535-6108 [Print] United States
• PMID: 15050914 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ADW 742
• Antineoplastic Agents
• Enzyme Inhibitors
• Pyrimidines
• Pyrroles
• Vascular Endothelial Growth Factor A
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1

Topics

• Antineoplastic Agents
• Bone Marrow (metabolism)
• Enzyme Inhibitors (pharmacology)
• Flow Cytometry
• Gene Expression Profiling
• Hematologic Neoplasms (drug therapy, metabolism)
• Humans
• Insulin-Like Growth Factor I (metabolism)
• Multiple Myeloma
• Neoplasms (drug therapy, metabolism)
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• Receptor, IGF Type 1 (antagonists & inhibitors, metabolism)
• Transplantation, Heterologous (pathology)
• Vascular Endothelial Growth Factor A (metabolism)