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Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future
Aaron Simpson1, Wilfride Petnga1, Valentine M Macaulay1
1Department of Oncology, University of Oxford, Oxford, UK.
Abstract:
Despite a strong preclinical rationale for targeting the insulin-like growth factor (IGF) axis in cancer, clinical studies of IGF-1 receptor (IGF-1R)-targeted monotherapies have been largely disappointing, and any potential success has been limited by the lack of validated predictive biomarkers for patient enrichment. A large body of preclinical evidence suggests that the key role of the IGF axis in cancer is in driving treatment resistance, via general proliferative/survival mechanisms, interactions with other mitogenic signaling networks, and class-specific mechanisms such as DNA damage repair. Consequently, combining IGF-targeted agents with standard cytotoxic agents, other targeted agents, endocrine therapies, or immunotherapies represents an attractive therapeutic approach. Anti-IGF-1R monoclonal antibodies (mAbs) do not inhibit IGF ligand 2 (IGF-2) activation of the insulin receptor isoform-A (INSR-A), which may limit their anti-proliferative activity. In addition, due to their lack of specificity, IGF-1R tyrosine kinase inhibitors are associated with hyperglycemia as a result of interference with signaling through the classical metabolic INSR-B isoform; this may preclude their use at clinically effective doses. Conversely, IGF-1/IGF-2 ligand-neutralizing mAbs inhibit proliferative/anti-apoptotic signaling via IGF-1R and INSR-A, without compromising the metabolic function of INSR-B. Therefore, combination regimens that include these agents may be more efficacious and tolerable versus IGF-1R-targeted combinations. Herein, we review the preclinical and clinical experience with IGF-targeted therapies to-date, and discuss the rationale for future combination approaches as a means to overcome treatment resistance.
Insights
Targeting the insulin-like growth factor (IGF) axis shows promise for overcoming cancer treatment resistance. Combination therapies involving IGF-targeted agents may offer improved efficacy and tolerability compared to monotherapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The insulin-like growth factor (IGF) axis is crucial in cancer, promoting proliferation and treatment resistance.
- Clinical trials of IGF-1 receptor (IGF-1R)-targeted monotherapies have yielded disappointing results due to a lack of predictive biomarkers.
- Preclinical data highlight the IGF axis's role in resistance mechanisms, including DNA repair and crosstalk with other signaling pathways.
Purpose of the Study:
- To review preclinical and clinical data on IGF-targeted cancer therapies.
- To explore the rationale for combining IGF-targeted agents with other treatment modalities.
- To discuss strategies for overcoming treatment resistance using IGF-axis modulation.
Main Methods:
- Review of preclinical studies on IGF axis signaling in cancer.
- Analysis of clinical trial outcomes for IGF-1R-targeted monotherapies and combination therapies.
- Evaluation of different IGF-targeting strategies, including monoclonal antibodies and tyrosine kinase inhibitors.
Main Results:
- IGF-1R-targeted monotherapies have shown limited clinical success.
- IGF-1R monoclonal antibodies may be limited by their inability to block IGF-2/INSR-A signaling.
- IGF-1R tyrosine kinase inhibitors can cause hyperglycemia due to off-target effects on INSR-B.
- IGF-1/IGF-2 ligand-neutralizing antibodies show potential for combination therapy due to broader target engagement and better tolerability.
Conclusions:
- Combination regimens involving IGF-targeted agents are a promising strategy to overcome cancer treatment resistance.
- Ligand-neutralizing antibodies targeting both IGF-1 and IGF-2 may offer superior efficacy and tolerability compared to IGF-1R-specific agents.
- Future research should focus on optimizing combination strategies and identifying predictive biomarkers for IGF-targeted therapies.
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