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Endoglin-targeted cancer therapies: current status and opportunities
Subinuer Abudukelimu1, Hao Dang1, Lukas J A C Hawinkels1
1Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
Introduction:
Endoglin has been extensively studied as an anti-angiogenic target, with preclinical work highlighting its critical role in tumor vasculature. TRC105 (carotuximab), a monoclonal antibody against endoglin, progressed through multiple clinical trials and was well tolerated, yet outcomes were disappointing, revealing a gap between preclinical findings and patient benefit. Recent insights into endoglin biology in the tumor microenvironment suggest that more precise, informed strategies are needed to fully realize its therapeutic potential.
Areas Covered:
This review summarizes key advances in endoglin biology, including its endothelial and non-endothelial roles and context-dependent effects across tumor and stromal compartments. We discuss preclinical therapeutic strategies and clinical trial experience with TRC105 and examine the translational challenges and future considerations needed to achieve potential clinical benefit.
Expert Opinion:
Preclinical studies have greatly advanced our understanding of endoglin biology, but the key challenge lies in identifying the biologic context where endoglin drives tumor progression. Future progress requires a deeper mechanistic resolution of endoglin's roles across tumor type and disease stage, along with the development of biomarkers incorporating spatial expression patterns. Successful translation will depend on matching endoglin-targeted therapy to patients and tumor ecosystems most likely to benefit, shifting from broad anti-angiogenic application to precision stromal targeting.
Insights
Endoglin (CD105) targeting shows promise in preclinical models but clinical trials with TRC105 yielded disappointing results. Future strategies require precision targeting of endoglin
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Endoglin (CD105) is a key regulator of angiogenesis and tumor vasculature.
- Preclinical studies demonstrated endoglin's critical role in tumor progression.
- TRC105 (carotuximab), an anti-endoglin antibody, showed poor clinical outcomes despite good tolerability.
Purpose of the Study:
- To review advances in endoglin biology within the tumor microenvironment.
- To analyze preclinical and clinical data for endoglin-targeted therapies.
- To identify strategies for improving therapeutic efficacy.
Main Methods:
- Literature review of preclinical studies on endoglin.
- Analysis of clinical trial data for TRC105.
- Examination of endoglin's roles in endothelial and non-endothelial cells.
Main Results:
- Endoglin has context-dependent roles in tumor and stromal compartments.
- Translational challenges exist between preclinical findings and patient benefit.
- TRC105 trials highlighted a gap in understanding endoglin's therapeutic window.
Conclusions:
- Deeper mechanistic understanding of endoglin's function is needed.
- Biomarkers incorporating spatial expression are crucial for patient selection.
- Precision targeting of endoglin in specific tumor ecosystems is the future direction.
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