title: Can we unlock the potential of IGF-1R inhibition in cancer therapy?
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.
authors.affiliation: St Catherine's College, University of Oxford, Manor Road, Oxford OX1 3UJ, UK. Electronic address: helen.king@stcatz.ox.ac.uk.
authors.forename: Helen
authors.initials: H
authors.lastname: King
authors.affiliation: Department of Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK. Electronic address: taleksic13@googlemail.com.
authors.forename: Tamara
authors.initials: T
authors.lastname: Aleksic
authors.affiliation: Division of Medical Oncology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA. Electronic address: Haluska.Paul@mayo.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.affiliation: 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.
authors.forename: Valentine M
authors.initials: VM
authors.lastname: Macaulay
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D002986:Clinical Trials as Topic; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D017526:Receptor, IGF Type 1
keywords: IGF; IGF-1R cancer therapy; Predictive biomarker; Therapeutic antibody; Type 1 IGF receptor; Tyrosine kinase inhibitor