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Investigational Notch and Hedgehog inhibitors--therapies for cardiovascular disease
Eileen M Redmond1, Shaunta Guha, Dermot Walls
1University of Rochester, Department of Surgery, 601 Elmwood Ave, Box SURG, Rochester, NY 14642, USA.
Introduction:
During the past decade, a variety of Notch and Hedgehog pathway inhibitors have been developed for the treatment of several cancers. An emerging paradigm suggests that these same gene regulatory networks are often recapitulated in the context of cardiovascular disease and may now offer an attractive target for therapeutic intervention.
Areas Covered:
This article briefly reviews the profile of Notch and Hedgehog inhibitors that have reached the preclinic and clinic for cancer treatment and discusses the clinical issues surrounding targeted use of these inhibitors in the treatment of vascular disorders.
Expert Opinion:
Preclinical and clinical data using pan-Notch inhibitors (γ-secretase inhibitors) and selective antibodies to preferentially target notch receptors and ligands have proven successful but concerns remain over normal organ homeostasis and significant pathology in multiple organs. By contrast, the Hedgehog-based drug pipeline is rich with more than a dozen Smoothened (SMO) inhibitors at various stages of development. Overall, refined strategies will be necessary to harness these pathways safely as a powerful tool to disrupt angiogenesis and vascular proliferative phenomena without causing prohibitive side effects already seen with cancer models and patients.
Insights
Notch and Hedgehog pathway inhibitors show promise for cardiovascular disease, building on cancer research. Careful strategies are needed to manage side effects and ensure safe therapeutic use in vascular disorders.
Area of Science:
- Oncology
- Cardiovascular Medicine
- Pharmacology
Background:
- Notch and Hedgehog pathways are crucial in cancer, with inhibitors developed for treatment.
- These pathways are increasingly recognized as relevant in cardiovascular disease.
- This presents an opportunity for novel therapeutic interventions in vascular disorders.
Purpose of the Study:
- To review Notch and Hedgehog inhibitors used in cancer treatment.
- To discuss clinical considerations for using these inhibitors in vascular disorders.
- To explore the potential and challenges of targeting these pathways for cardiovascular conditions.
Main Methods:
- Review of preclinical and clinical data on Notch inhibitors (γ-secretase inhibitors, antibodies).
- Examination of the Hedgehog inhibitor drug pipeline (SMO inhibitors).
- Analysis of clinical issues and safety concerns associated with pathway inhibition.
Main Results:
- Pan-Notch inhibitors show success but raise concerns about organ homeostasis and pathology.
- A substantial number of Smoothened (SMO) inhibitors for the Hedgehog pathway are in development.
- Targeted use of these inhibitors in cancer has yielded mixed results regarding side effects.
Conclusions:
- Refined strategies are essential for safe application of Notch and Hedgehog pathways.
- The goal is to disrupt angiogenesis and vascular proliferation without severe side effects.
- Balancing therapeutic benefits with potential pathologies is key for future treatments.
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