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Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma

Stefanie de Groot1, Bas Röttgering2, Hans Gelderblom1

  • 1Department of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

Cancers
|December 2, 2020
PubMed

Insights

Insulin-like growth factor-1 receptor (IGF1R) inhibitors show promise in preclinical cancer models but face resistance in clinical trials. Strategies to overcome resistance, including targeting insulin signaling, may improve therapeutic outcomes.

Area of Science:

  • Oncology
  • Endocrinology
  • Pharmacology

Background:

  • Insulin-like growth factor-1 receptor (IGF1R) inhibitors demonstrate efficacy in preclinical cancer studies.
  • Clinical trials show limited benefit, with notable exceptions in Ewing sarcoma patients exhibiting sustained responses.
  • Mechanisms of resistance to IGF1R inhibition remain largely unelucidated.

Purpose of the Study:

  • To review potential mechanisms of resistance to IGF-targeted therapies.
  • To discuss clinical trial outcomes for IGF1-targeted therapies.
  • To explore strategies for overcoming identified resistance mechanisms.

Main Methods:

  • Literature review of preclinical and clinical studies on IGF1R inhibitors.
  • Analysis of proposed resistance mechanisms, including insulin signaling and feedback loops.
  • Evaluation of clinical trial data and therapeutic strategies.

Main Results:

  • Resistance mechanisms may involve activated insulin signaling, growth hormone (GH)-mediated feedback loops, and autocrine loops.
  • Clinical trials have yielded mixed results, highlighting the need for improved therapeutic strategies.
  • Ewing sarcoma cells predominantly express the insulin receptor A (IRA), distinct from the insulin receptor B (IRB) in healthy tissues.

Conclusions:

  • Targeting insulin signaling, by lowering plasma insulin levels or blocking its activity, could enhance cancer therapy in combination with IGF1 inhibition.
  • Developing specific IRA inhibitors may offer a targeted approach for Ewing sarcoma treatment due to its distinct receptor expression profile.
Keywords:
Ewing sarcomaGHIGF1IGF1RIGF2INSRIRAIRBinsulinresistance

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