Chordoma Foundation

IGF-1R

Insulin Growth Factor-1 Receptor is a receptor tyrosine kinase (RTK). RTKs code for proteins on the surface of the cell that become activated when they bind to their ligands.

Ligands: IGF-1 and IGF-2

IGF-1R
is known to signal through the PI3k-Akt-mTOR and MAPK pathways, both of which are involved in regulating cell cycle processes of apoptosis, proliferation, migration, and survival. IGF-1R expression can play a role in transformation events and enhance cell survival, and overexpression of IGF-1R has been linked to tumor development and metastasis as well as to tumor resistance to cytotoxic therapies.1

IGF-1R in Chordoma

Studies indicate that IGF-1R and its ligands, particularly IGF-1, are consistently expressed in chordoma and that the IGF-1R/IGF-1 signaling pathway is activated in a subset of chordomas. Pathways downstream of IGF-1R (notably PI3k/Akt/mTOR) are also activated in chordoma. This page contains a summary of published research evaluating IGF-1R expression and activation in chordoma. Though drugs that inhibit IGF-1R have not been studied in chordoma model systems or tested in patients, they have been evaluated in other cancer types and have emerged as promising treatment agents.2

Molecular Evidence


Gene Expression

IGF-1R gene expression is higher in chordoma than in fetal nucleus pulposus control tissue.3

Gene Mutation

A heterozygous IGF-1R UTR point mutation was identified in one patient tumor and a subclonal missense mutation in another patient tumor using exome sequencing.4

Protein Expression

Expression of IGF-1R and its ligands IGF-1 and IGF-2 is detected in the majority of chordoma samples tested.1 5 6 7

Protein Activation

p-IGF-1R, the phosphorylated, activated form of the IGF-1R protein, is detected in a subset of conventional chordomas.8 Hypermethylation of the KL tumor suppressor gene (which normally inhibits IGF-1/IGF-1R signaling) has been observed in 10/10 chordomas tested.9

Clinical Evidence


Case Report

  • Linsitinib + Erlotinib: A durable objective response was observed in a patient with spinal chordoma that had recurred. IGF1-R measurements in primary tumor, recurrence, and post-trial recurrence indicate the presence of nuclear IGF-1R, which may signify dependence on IGF-1R and sensitivity to IGF axis inhibition.5

Phase I Trials

  • Linsitinib + Erlotinib: A spinal chordoma patient was among the 5 (of 75) evaluable patients with advanced solid tumors who experienced partial response to treatment with IGF1R inhibitor Linsitinib (OSI-906) and EGFR inhibitor erlotinib. Partial response was sustained 268+ weeks after treatment initiation.10


References

1.
Scheipl S, Froehlich E, Leithner A, et al. Does insulin-like growth factor 1 receptor (IGF-1R) targeting provide new treatment options for chordomas? A retrospective clinical and immunohistochemical study. Histopathology. 2012;60(6):999-1003. [PubMed]
2.
Salisbury A, Macaulay V. Development of molecular agents for IGF receptor targeting. Horm Metab Res. 2003;35(11-12):843-849. [PubMed]
3.
Chen H, Zhang K, Lu J, Wu G, Yang H, Chen K. Comprehensive analysis of mRNA-lncRNA co-expression profile revealing crucial role of imprinted gene cluster DLK1-MEG3 in chordoma. Oncotarget. 2017;8(68):112623-112635. [PMC]
4.
Liang W, Dardis C, Helland A, et al. Identification of therapeutic targets in chordoma through comprehensive genomic and transcriptomic analyses. Cold Spring Harb Mol Case Stud. October 2018. [PubMed]
5.
Aleksic T, Browning L, Woodward M, et al. Durable Response of Spinal Chordoma to Combined Inhibition of IGF-1R and EGFR. Front Oncol. 2016;6:98. [PubMed]
6.
Mitsuhashi T, Watanabe M, Sasano H, Ono M. The expression of insulin-like growth factor-1(IGF-1), IGF- 1 receptor and transforming growth factor-β in chordoma [poster presentation]. . XXVI Congress of the International Academy of Pathology. https://www.nature.com/modpathol/journal/v19/n3s/pdf/3800862a.pdf. Published September 2006.
7.
Mitsuhashi T, Asanuma H, Hasegawa T. Insulin-Like Growth Factor (IGF)-I and IGF-I Receptor (IGF-IR) Are Consistently Expressed in the Most of Chordomas [abstract]. Annual Meeting. https://www.nature.com/modpathol/journal/v21/n1s/pdf/3801027a.pdf.
8.
Sommer J, Itani D, Homlar K, et al. Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma. J Pathol. 2010;220(5):608-617. [PubMed]
9.
Rinner B, Weinhaeusel A, Lohberger B, et al. Chordoma characterization of significant changes of the DNA methylation pattern. PLoS One. 2013;8(3):e56609. [PubMed]
10.
Macaulay V, Middleton M, Eckhardt S, et al. Phase I Dose-Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors. Clin Cancer Res. 2016;22(12):2897-2907. [PubMed]