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IGF-IR Targeted Therapy: Past, Present and Future.

Joseph A M J L Janssen1, Aimee J Varewijck1

  • 1Department of Internal Medicine, Division of Endocrinology, Erasmus MC , Rotterdam , Netherlands.

Frontiers in Endocrinology
|January 8, 2015
PubMed
Summary

Targeting the insulin-like growth factor I receptor (IGF-IR) for cancer therapy has failed due to complex signaling pathways. The insulin receptor isoform A (IR-A) activation by IGF-II bypasses IGF-IR inhibition, hindering treatment success.

Keywords:
IGF-I receptorIGF-IR antibodiesIGF-IR targeted therapycancerhyperglycemiainsulin receptor-Ainsulin receptor-B

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Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The insulin-like growth factor I receptor (IGF-IR) is a target for anti-cancer therapies.
  • Clinical trials using IGF-IR targeted therapies have yielded disappointing results.

Purpose of the Study:

  • To review potential reasons for the failure of IGF-IR targeted therapy in human cancers.
  • To explore alternative strategies for successful IGF-IR targeted cancer treatment.

Main Methods:

  • Review of existing literature on IGF-IR signaling pathways and targeted therapies.
  • Analysis of complex intracellular signaling networks and resistance mechanisms.

Main Results:

  • Intracellular signaling pathways are complex and interconnected, not linear.
  • Insulin receptor isoform A (IR-A) activation by IGF-II can bypass IGF-IR inhibition.
  • Reduced IGF-IR expression, drug-induced hyperglycemia/hyperinsulinemia, and circulating IGF-IRs may impede therapy.
  • IGF-IR targeted therapy can lead to hyperglycemia and hyperinsulinemia, potentially stimulating cancer growth.

Conclusions:

  • IGF-IR targeted therapy has limitations due to pathway complexity and resistance mechanisms.
  • Combined inhibition of IGF-IR and IR-A may be necessary for effective cancer treatment.
  • Development of biasing agonists targeting downstream IGF-IR effects could improve therapeutic outcomes.