Keloids Clinical Trial
Official title:
Phase II Trial of Sorafenib in Patients With Extensive Keloids
Treatment of keloid disorder is an area of unmet medical need. Current treatments for keloid
partially address small and localized keloids, yet there are no wholly satisfactory or
effective treatments for patients with extensive keloids. Such patients may benefit from
effective systemic treatments.
Sorafenib has the potential to regulate the three known dysregulated biological pathways in
keloid tissue.
Dysregulation of several intracellular pathways have been reported by various investigators.
[A] Dysregulated apoptosis pathway: p53 mutations have been found in both hypertrophic scar
and keloids fibroblasts from cultured cells to various extents. p53 plays a central role in
the DNA damage response by inducing cell cycle arrest and/or apoptotic cell death. Time
course experiments making cell cultures at different times to investigate the phenomenon of
apoptosis and its involvement in the process of pathological scarring in both hypertrophic
scars and keloid indicate to dysregulation of apoptotic pathways in Keloid tissue.
[B]Dysregulated TGF- β signaling: Transforming growth factor- β1 (TGF- β1) is well known as
the crucial fibrogenic cytokine promoting ECM production and tissue fibrosis in keloid
forming [9]. TGF- β1 is an essential profibrotic cytokine for collagen synthesis, and it is
well known to increase mRNA expression of procollagen I. Administration of TGF- β1 resulted
in a dramatic increase in intracellular collagen I levels in keloid fibroblasts. Due to the
close relationship between TGF- β signaling and the production of collagen, blocking TGF- β
signaling has the potential of repressing fibroblast proliferation and collagen synthesis,
thereby preventing the formation of keloids.
[C]Dysregulated VEGF signaling pathway: VEGF (Vascular endothelial growth factor), one of
the most widely studied secreted factors involved in angiogenesis, has been implicated as
crucial to normal and pathological wound healing [18]. Gira et al. [19] indicated that VEGF
production is abundant in the underlying dermis of keloids. In vitro studies have indicated
that VEGF is expressed at higher levels in keloid-derived Fibroblasts than in normal skin
Fibroblasts.
Sorafenib is an orally active multikinase inhibitor and has been reported to be an effective
inhibitor of apoptosis, TGF-β signaling and VEGF pathway signaling, making it an ideal drug
to test in the setting of extensive keloid disorder.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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