Investigational IGF1R inhibitors in early stage clinical trials for cancer therapy

ABSTRACT

Introduction: The insulin-like growth factors (IGFs) are a family of secreted peptide hormones with important roles in different cellular and organism functions. The biological activities of the IGFs are mediated by the IGF1 receptor (IGF1R), a cell surface, tyrosine kinase-containing heterotetramer that is linked to numerous cytoplasmic signaling cascades. The IGF1R displays potent antiapoptotic, pro-survival capacities and plays a key role in malignant transformation. Research has identified the IGF1R as a candidate therapeutic target in cancer.

Areas covered: We offer a synopsis of ongoing efforts to target the IGF axis for therapeutic purposes. Our review includes a digest of early experimental work that led to the identification of IGF1R as a candidate therapeutic target in oncology.

Expert opinion: Targeting of the IGF axis has yielded disappointing results in phase III trials, but it is important to learn from this to improve future trials in a rational manner. The potential of anti-IGF1R antibodies and small molecular weight inhibitors, alone or in combination with chemotherapy or other biological agents, should be investigated further in randomized studies. Moreover, the implementation of predictive biomarkers for patient selection will improve the outcome of future trials. Emerging personalized medicine could have a major impact on IGF1R targeting.

KEYWORDS:

• Insulin-like growth factor-1 (IGF1)
• IGF1 receptor (IGF1R)
• targeted therapy
• cancer

Article highlights

• The IGF hormonal network plays an important role in malignant transformation.

• The IGF1R has emerged as a promising therapeutic target in cancer.

• IGF1R antibodies and small inhibitory molecules were tested in recent years in Phase I/III clinical studies for various solid tumors and hematological malignancies.

• Results of Phase I/II studies indicate that monotherapy conferred stability of disease rather than responses.

• There is a significant consensus that combination of IGF1R therapy along with classical drugs or other biological therapies will lead to a major leap in the field.

• It is necessary to identify predictive biomarkers that could assist in selecting patients who could benefit from IGF1R-directed therapies.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.