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Review
. 2010 Nov 20;28(33):4985-95.
doi: 10.1200/JCO.2009.27.5040. Epub 2010 Oct 25.

Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer

Robert G Maki  1
Affiliations
Review

Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer

Robert G Maki. J Clin Oncol. .

Abstract

Insulin-like growth factors were discovered more than 50 years ago as mediators of growth hormone that effect growth and differentiation of bone and skeletal muscle. Interest of the role of insulin-like growth factors in cancer reached a peak in the 1990s, and then waned until the availability in the past 5 years of monoclonal antibodies and small molecules that block the insulin-like growth factor 1 receptor. In this article, we review the history of insulin-like growth factors and their role in growth, development, organism survival, and in cancer, both epithelial cancers and sarcomas. Recent developments regarding phase I to II clinical trials of such agents are discussed, as well as potential studies to consider in the future, given the lack of efficacy of one such monoclonal antibody in combination with cytotoxic chemotherapy in a first-line study in metastatic non-small-cell lung adenocarcinoma. Greater success with these agents clinically is expected when combining the agents with inhibitors of other cell signaling pathways in which cross-resistance has been observed.

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Conflict of interest statement

Author's disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Insulin-like growth factor receptor 1 (IGF1R) signaling pathway and potential mechanisms of resistance to IGF1R blockade (red asterisks). Heterodimers between IGF1R and related proteins are one mechanism of resistance to IGF1R inhibitors, and, conversely, signaling through IGF1R is one mechanism of resistance through human epidermal growth factor receptor 2 (HER2) and other epidermal growth factor receptor (EGFR) family members. White circles represent kinases, black circles phosphatases. Blue X indicates signaling points for which there are inhibitors in clinical trials or commercially available. Green hexagon with R represents sirolimus (rapamycin). Red arrows represent autophosphorylation of receptor tyrosine kinases (RTKs). Red dots represent phosphate groups. A list of clinical trials involving single-agent IGF1R inhibitors is included in Appendix Table A1 (online only). IGFBPs, insulin-like growth factor binding proteins; RXR, retinoid X receptor.
Fig 2.
Fig 2.
Relative expression of insulin growth factor 2 (IGF2) protein by immunohistochemistry in different sarcoma subtypes. The number of samples examined for each subtype is indicated in parentheses. SFT, solitary fibrous tumor; HPC, hemangiopericytoma; MPNST, malignant peripheral-nerve sheath tumor; HGUPS, high-grade undifferentiated pleomorphic sarcoma; MFH, malignant fibrous histiocytoma; PVNS, pigmented villonodular synovitis; TGCT, tenosynovial giant cell tumor.
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