Investigational Notch and Hedgehog inhibitors--therapies for cardiovascular disease.
BACKGROUND
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.


METHODS
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.


CONCLUSIONS
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.
University of Rochester, Department of Surgery, 601 Elmwood Ave, Box SURG, Rochester, NY 14642, USA.
Eileen M
EM
Redmond
Shaunta
S
Guha
Dermot
D
Walls
Paul A
PA
Cahill
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000503:physiopathology*; D015507:Drugs, Investigational / Q000494:pharmacology*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D053823:Hedgehog Proteins; D051880:Receptors, Notch