A Pilot Phase II Study of Valproic Acid for Treatment of Low-Grade Neuroendocrine Carcinoma

Mohammed, Tabraiz A.; Holen, Kyle D.; Jaskula-Sztul, Renata; Mulkerin, Daniel; Lubner, Sam Joseph; Schelman, William R.; Eickhoff, Jens; Chen, Herbert; LoConte, Noelle K.

doi:10.1634/theoncologist.2011-0031

Cited by 78 publications

(55 citation statements)

References 34 publications

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“…As a result, targeting of deregulated epigenetic mechanisms has emerged as a possible novel treatment strategy in NETs [20,21]. Valproic acid (VPA), an inhibitor of class I and class IIa HDACs, has recently been tested in phase II studies on patients with metastatic NETs with promising results [22]. Well established as an anti-seizure drug, VPA has emerged as a promising anti-tumour agent, combining low cost with good clinical tolerability [23].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells

et al. 2015

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Background/Aims: Histone deacetylases (HDACs) modulate lysine acetylation on histones and are frequently deregulated in cancer. HDAC inhibitors with potent anti-tumour effects have been developed and are now being tested in clinical trials. The aim of this study was to investigate the effects of valproic acid (VPA), an inhibitor of class I and class IIa HDACs, on neuroendocrine tumour (NET) cell growth. Methods: Three NET cell lines, GOT1 (small intestinal), KRJ-I (small intestinal), and BON (pancreatic), were treated with VPA and examined with respect to cell viability, cell cycle arrest, apoptosis, and global transcriptional response. Results: We found that VPA induced a dose-dependent growth inhibition of NET cells in vitro, which was mainly due to activation of extrinsic and intrinsic apoptotic pathways. VPA induced a major transcriptional response by altering the expression of 16-19% of the protein-coding genes in NET cell lines. Pathway analysis allowed the prediction of alterations in key regulatory pathways, e.g. activation of TGF-β1, FOXO3, p53 signalling, and inhibition of MYC signalling. Analysis of GOT1 xenografts showed reduced growth and reduced Ki-67 index, as well as an increase in apoptosis and necrosis after VPA treatment. Conclusions: We found that VPA treatment has a cytotoxic effect on NET cells of intestinal and pancreatic origin. There are several mechanisms by which VPA kills NET cells, which suggests the possibility of combination therapy. We propose that epigenetic therapy with HDAC inhibitors should be evaluated further in patients with NET disease.

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Section: Introductionmentioning

confidence: 99%

Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells

et al. 2015

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“…Overall, treatment with VPA was well tolerated. 81 Although the number of patients was small, this study demonstrates that activation of the Notch1 pathway could lead to clinical responses in this patient population.…”

Section: Epigenetic Profile Of Net and Drug Treatmentmentioning

confidence: 79%

Epigenetic changes in gastroenteropancreatic neuroendocrine tumours

et al. 2014

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An understanding of epigenetic drivers of tumorigenesis has developed rapidly during the last years. The identification of these changes including DNA methylation and histone modifications in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) is a step forward in trying to define underlying biologic processes in this heterogeneous disease. The reversible nature of these changes represents a potential therapeutic target. We present an overview of the current knowledge of epigenetic alterations related to GEP-NETs, focusing on the influence and impact these changes have on pathogenesis and prognosis. The potential role of demethylating agents in the management of this patient population is discussed.

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“…Notch1 signalling was absent in all tumours before treatment and was up-regulated with VPA. One patient had an unconfirmed partial response and four had stable disease, tumour markers improved in five out of seven (Mohammed et al 2011). This well-tolerated agent may have a role in the management of low-grade NETs and is currently being trialled in many different tumour types.…”

Section: Early Phase Clinical Trials Of Hdacis In Net Are Inconclusivementioning

confidence: 91%

Neuroendocrine tumours: cracking the epigenetic code

Karpathakis¹,

Dibra²,

Thirlwell³

2013

Endocrine-Related Cancer

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The field of epigenetics has evolved rapidly over recent years providing insight into the tumorigenesis of many solid and haematological malignancies. Determination of epigenetic modifications in neuroendocrine tumour (NET) development is imperative if we are to improve our understanding of the biology of this heterogenous group of tumours. Epigenetic marks such as DNA methylation at RASSF1A are frequent findings in NETs of all origins and may be associated with worse prognosis. MicroRNA signatures and histone modifications have been identified which can differentiate subtypes of NET and distinguish NET from adenocarcinoma in cases of diagnostic uncertainty. Historically, candidate genedriven approaches have yielded limited insight into the epigenetics of NET. Recent progress has been facilitated by development of high-throughput tools including second-generation sequencing and arrays for analysis of the 'epigenome' of tumour and normal tissue, permitting unbiased approaches such as exome sequencing that identified mutations of chromatin-remodelling genes ATRX/DAXX in 44% of pancreatic NETs. Epigenetic changes are reversible and therefore represent an attractive therapeutic target; to date, clinical outcomes of epigenetic therapies in solid tumours have been disappointing; however, in vitro studies on NETs are promising and further clinical trials are required to determine utility of this class of novel agents. In this review, we perform a comprehensive evaluation of epigenetic changes found in NETs to date, including rare NETs such as phaeochromocytoma and adrenocortical tumours. We suggest priorities for future research and discuss potential clinical applications and novel therapies.

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A Pilot Phase II Study of Valproic Acid for Treatment of Low-Grade Neuroendocrine Carcinoma

Cited by 78 publications

References 34 publications

Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells

Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells

Epigenetic changes in gastroenteropancreatic neuroendocrine tumours

Neuroendocrine tumours: cracking the epigenetic code

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