The insulin-like growth factor 1 receptor (IGF-1R) and its associated
signalling system provoked considerable interest over recent years as a therapeutic target
in cancer. Whilst preclinical evidence for the efficacy of IGF-1R pathway inhibitors is
strong, only very modest signals of activity have been observed in the clinical setting
thus far. This has prompted several pharmaceutical companies to terminate their
respective drug development programmes. Far from representing an ineffective strategy,
we believe that the lack of efficacy hitherto observed in unselected trials is at least
partially due to a failure to restrict the use of these inhibitors to those most likely to
benefit. Both patient and tumor factors, including the complex signalling networks that
interact with the IGF-1R pathway, are important mediators of response. In this updated
chapter, we focus on the preclinical studies and retrospective clinical data that have
attempted to identify biomarkers that predict for efficacy and resistance. Some intriguing
results are beginning to emerge which should, in time, prompt for a reappraisal of
promising agents and lead to a second generation of clinical trials, this time in
populations enriched for those likely to benefit. In particular, we discuss the available
clinical data for the IGF-1R antibodies figitumumab (CP-751,871), cixutumumab (IMCA12),
ganitumab (AMG-479), dalotuzumab (MK-0646), robatumumab (R1507), the
IGF-1R tyrosine kinase inhibitors linsitinib (OSI-906), XL228 and AXL1717, and also
consider some more recently developed agents, including the IGF-1/IGF-2 neutralising
antibody MEDI-573. Finally, we review some recent patents in the field, including IGF-
1R combination therapeutics and biomarkers.
Keywords: Antibody, biomarker, cancer, colorectal, EGFR, growth hormone,
HER2, insulin-like growth factor, insulin-like growth factor inhibitor, IGF-1R,
IGF-1, IGF-2, IR-A, IR-B, insulin receptor, lung, personalised medicine, sarcoma,
targeted therapy, tyrosine kinase inhibitor.
