Epigenetic-based targeted therapies for well-differentiated pancreatic neuroendocrine tumors: recent advances and future perspectives

ABSTRACT

Introduction

Well-differentiated pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of primary tumors of the endocrine pancreas. Dysregulation of chromatin remodeling, gene expression alteration, global DNA hypomethylation of non-coding regions, DNA hypermethylation and silencing of tumor suppressor gene promoters are frequent epigenetic changes in PanNETs. These changes exert a role in neoplastic transformation and progression. As epigenetic mechanisms, converse to genetic mutations, are potentially reversible, they are an interesting and promising therapeutic target for the treatment of PanNETs.

Areas covered

We reviewed main epigenetic alterations associated with the development, biological and clinical features and progression of PanNETs, as well as emerging therapies targeting epigenetic changes, which may prove effective for the treatment of human PanNETs.

Expert opinion

Constant advances in the PanNET medical approach, as reported in the clinical and therapeutic recommendations of ESMO, improved the overall survival of patients over the years. However, over 60% of the patients with metastatic disease still have poor prognosis. Epigenetic regulator drugs, currently approved to treat some human malignancies, that showed anti-tumoral activity also on PanNETs, in pre-clinical and clinical studies, could concur to ameliorate the prognosis and OS of advanced and metastatic PanNET, in combination with surgery and currently employed medical therapies.

KEYWORDS:

• Chromatin remodeling
• DNA methylation
• epigenetic pathway inhibitors
• histone modifications
• MEN1 gene
• well-differentiated pancreatic neuroendocrine tumors (panNETs)

Article highlights

• PanNETs have a mortality rate of about 60% at ten years after diagnosis.

• About 85% of the cases are non-functioning silent tumors usually discovered at the advanced and/or metastatic stage.

• Surgical excision is the most employed therapy, but it is poorly curative in the 40–50% of the cases with advanced and/or metastatic cancers or in syndromic forms with multiple and relapsing cancers.

• Tumor aggressiveness depends on the tumor stage at discovery and on the molecular status of the neoplasm(s).

• The understanding of the role of genetic- and epigenetic-driven molecular signatures of different PanNETs in tumorigenesis and tumor aggressiveness would help identify patients who would benefit from a specific therapy and better tailor a personalized clinical management.

• Epigenetic changes are a common molecular hallmark of sporadic and syndromic PanNETs and they are shown to have a central pro-oncogenic role in the tumorigenesis.

• Targeting epigenetic pathways, and reversing pro-oncogenic epigenetic changes, could be of therapeutic value to prevent PanNET proliferation and progression.

• Epigenetic pathway inhibitors are currently successfully employed in some human malignancies and promising preclinical data indicated them as suitable therapeutic options for well-differentiated PanNETs, mostly HDACIs.

Declaration of interest statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, and royalties.

Reviewer disclosures

Peer reviewers of this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.