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Clinical Trial
. 2011;16(6):835-43.
doi: 10.1634/theoncologist.2011-0031. Epub 2011 May 31.

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

Tabraiz A Mohammed  1 , Kyle D Holen, Renata Jaskula-Sztul, Daniel Mulkerin, Sam J Lubner, William R Schelman, Jens Eickhoff, Herbert Chen, Noelle K Loconte
Affiliations
Clinical Trial

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

Tabraiz A Mohammed et al. Oncologist. 2011.

Abstract

Introduction: 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.

Patients and methods: 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.

Results: 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.

Conclusion: . VPA activates Notch1 signaling in vivo and may have a role in treating low-grade NETs.

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Conflict of interest statement

Disclosures: Tabraiz A. Mohammed: None; Kyle D. Holen: Employment/leadership position: Abbott Laboratories; Ownership interest: Abbott Laboratories; Renata Jaskula-Sztul: None; Daniel Mulkerin: None; Sam J. Lubner: None; William R. Schelman: None; Jens Eickhoff: None; Herbert Chen: None; Noelle K. LoConte: None.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.

Figures

Figure 1.
Figure 1.
Waterfall plot of tumor marker change from baseline. The majority of patients experienced an improvement in their tumor markers with 3 out of 7 approaching a near 100% improvement from baseline.
Figure 2.
Figure 2.
Overall survival plotted by the Kaplan-Meier method. The median overall survival has not been reached after a maximum follow-up time of 21 months.
Figure 3.
Figure 3.
Progression-free survival (PFS) plotted by the Kaplan-Meier method. The median PFS time was 13 months.
Figure 4.
Figure 4.
Gene expression analysis for NOTCH1 in pretreatment and post-treatment biopsies. Each of pre-VPA and on VPA bars represents the mean of biopsies from four different patients. NOTCH1–3 expression folds were obtained by dividing normalized expressions of unknown samples (pre- or on VPA) by normalized expression of negative control comprising gastrointestinal carcinoid cell line (BON). Fold expression was then plotted as average ± SEM. The differences in NOTCH1 expressions between pre-VPA and on VPA treatment groups were statistically significant (p < .05). Abbreviation: VPA, valproic acid.
See this image and copyright information in PMC

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