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Cancer Treat Rev. 2014 Oct;40(9):1096-105. doi: 10.1016/j.ctrv.2014.07.004. Epub 2014 Aug 4.

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

Author information

1
St Catherine's College, University of Oxford, Manor Road, Oxford OX1 3UJ, UK. Electronic address: helen.king@stcatz.ox.ac.uk.
2
Department of Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK. Electronic address: taleksic13@googlemail.com.
3
Division of Medical Oncology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA. Electronic address: Haluska.Paul@mayo.edu.
4
Department of Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK; Oxford Cancer Centre, Churchill Hospital, Oxford OX3 7LE, UK. Electronic address: valentine.macaulay@oncology.ox.ac.uk.

Abstract

IGF-1R inhibitors arrived in the clinic accompanied by optimism based on preclinical activity of IGF-1R targeting, and recognition that low IGF bioactivity protects from cancer. This was tempered by concerns about toxicity to normal tissue IGF-1R and cross-reactivity with insulin receptor (InsR). In fact, toxicity is not a show-stopper; the key issue is efficacy. While IGF-1R inhibition induces responses as monotherapy in sarcomas and with chemotherapy or targeted agents in common cancers, negative Phase 2/3 trials in unselected patients prompted the cessation of several Pharma programs. Here, we review completed and on-going trials of IGF-1R antibodies, kinase inhibitors and ligand antibodies. We assess candidate biomarkers for patient selection, highlighting the potential predictive value of circulating IGFs/IGFBPs, the need for standardized assays for IGF-1R, and preclinical evidence that variant InsRs mediate resistance to IGF-1R antibodies. We review hypothesis-led and unbiased approaches to evaluate IGF-1R inhibitors with other agents, and stress the need to consider sequencing with chemotherapy. The last few years were a tough time for IGF-1R therapeutics, but also brought progress in understanding IGF biology. Even failed studies include patients who derived benefit; they should be investigated to identify features distinguishing the tumors and host environment of responders from non-responders. We emphasize the importance of incorporating biospecimen collection into trial design, and wording patient consents to allow post hoc analysis of trial material as new data become available. Such information represents the key to unlocking the potential of this approach, to inform the next generation of trials of IGF signalling inhibitors.

KEYWORDS:

IGF; IGF-1R cancer therapy; Predictive biomarker; Therapeutic antibody; Type 1 IGF receptor; Tyrosine kinase inhibitor

PMID:
25123819
PMCID:
PMC4196677
DOI:
10.1016/j.ctrv.2014.07.004
[Indexed for MEDLINE]
Free PMC Article

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