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: 4.87). 06/2011; 16(6):835-43. DOI: 10.1634/theoncologist.2011-0031
Source: PubMed


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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    • "On the other hand, for poorly-differentiated NECs of the pancreas, the NCCN guidelines and North American Neuroendocrine Tumor Society consensus guidelines (6) recommend combined chemotherapy with cisplatin and etoposide, one of the standard regimens employed for the treatment of small cell lung cancer. In addition, the efficacies of GEM and oral S-1 (7), bevacizumab (8), folinic acid, fluorouracil and irinotecan (9), valproic acid (10) and other treatments have also been reported. "
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    • "A pilot phase II study in eight patients with lowgrade NETs showed that VPA via oral administration and reaching a final serum concentration between 50 and 100 µg/ml could activate in vivo Notch1 signaling [83]. Most patients had little toxicity, with 50% displaying a stability in disease control [83]. Thus, VPAmediated Notch activation may play a key role in treating NET patients. "
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    ABSTRACT: Valproic acid (VPA), a well-known anti-epilepsy drug, has been currently applied as a novel anti-cancer agent in the investigation of cancer drug development. VPA can modulate multiple cell processes and tumor suppression by its involvement in various signaling pathways. VPA functions as a tumor suppressor against various cancers, mainly by acting as a histone deacetylase (HDAC) inhibitor. However, in certain types of cancers, VPA plays a different role by activating HDACs and reducing histone acetylation. Moreover, VPA was recently found involved in the regulation of Notch signaling. This Notch signaling plays a critical role in certain cancers and has dual functions, acting as either as a tumor suppressor in some cancers or an oncogene in some others. VPA up-regulates Notch signaling and subsequently reduces tumor growth in most investigated cancer cells, but is also found to down-regulate Notch signaling in hepatocelluler cancer cells. The newest findings showing that VPA up-regulates the expression of certain G protein-coupled receptors (GPCRs) provides a promising strategy to dramatically enhance anti-cancer efficacy when VPA is combined with receptor-targeted cytotoxic conjugates. VPA itself has few side effects and displays broad anti-cancer activity in many cancers, but its effect is very limited. Thus, VPA was used as an ideal adjuvant in combination with other anti-cancer agents such as celecoxib, bortezomib, irinotecan (CPT-11), paclitaxel, rapamycin (mTOR) inhibitor RAD001, clofarabine, lovastatin and gemcitabine. These agents, in combination and at lower doses, effectively augment synergistical effects on many cancers such as leukemia, neuroblastoma, breast cancer and prostate cancer glioblastoma, with many cases under clinical investigation. *
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