Article

A pilot phase II study of valproic acid for treatment of low-grade neuroendocrine carcinoma.

D.O., M.S., University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, Wisconsin 53792, USA. .
The Oncologist (impact factor: 3.91). 01/2011; 16(6):835-43. DOI:10.1634/theoncologist.2011-0031 pp.835-43
Source: PubMed

ABSTRACT Notch1 has been shown to be a tumor suppressor in neuroendocrine tumors (NETs). Previous in vitro studies in NET cell lines have also suggested that valproic acid (VPA), a histone deacetylase inhibitor, can induce Notch1 and that Notch1 activation correlates with a decrease in tumor markers for NETs. Thus, this study aimed to evaluate the role of VPA in treating NETs and to determine whether VPA induced the Notch signaling pathway signaling in vivo.
Eight patients with low-grade NETs (carcinoid and pancreatic) were treated with 500 mg of oral VPA twice a day with dosing adjusted to maintain a goal VPA level between 50 and 100 μg/mL. All patients were followed for 12 months or until disease progression.
Notch1 signaling was absent in all tumors prior to treatment and was upregulated with VPA. One patient had an unconfirmed partial response and was noted to have a 40-fold increase in Notch1 mRNA levels. Four patients had stable disease as best response. Tumor markers improved in 5 out of 7 patients. Overall, treatment with VPA was well tolerated.
. VPA activates Notch1 signaling in vivo and may have a role in treating low-grade NETs.

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Keywords

40-fold increase
 
7 patients
 
disease progression
 
goal VPA level
 
histone deacetylase inhibitor
 
induce Notch1
 
low-grade NETs
 
NET cell lines
 
neuroendocrine tumors
 
Notch1 activation correlates
 
Notch1 mRNA levels
 
Notch1 signaling
 
oral VPA
 
tumor markers
 
tumor suppressor
 
unconfirmed partial response
 
valproic acid
 
vitro studies
 
VPA activates Notch1 signaling
 
VPA induced