Promising targetable biomarkers in pancreatic neuroendocrine tumours

ABSTRACT

Introduction

In the treatment scenario of PanNETs-targeted therapies are desired but limited, as rarity and heterogeneity on PanNETs pose limitations to their development.

Areas covered

We performed a literature review searching for promising druggable biomarkers and potential treatments to be implemented in the next future. We focused on treatments which have already reached clinical experimentation, although in early phases. Six targets were identified, namely Hsp90, HIFa, HDACs, CDKs, uPAR, and DDR. Even though biological rational is strong, so far reported efficacy outcomes are quite disappointing. The reason of that should be searched in the patients’ heterogeneity, lack of biomarker selection, poor knowledge of interfering mechanisms as well as difficulties in patients accrual. Moreover, different ways to assess treatment efficacy should be considered, other than response rate, in light of the more indolent nature of NETs.

Expert opinion

Development of targeted treatments in PanNETs is still an uncovered area, far behind other more frequent cancers. Rarity of NETs led to accrual of unselected populations, possibly jeopardizing the drug efficacy. Better patients’ selection, both in terms of topography, grading and biomarkers is crucial and will help understanding which role targeted therapies can really play in these tumors.

GRAPHICAL ABSTRACT

KEYWORDS:

• NETs
• NENs
• PanNETs
• target therapy
• Hsp90
• HIFa
• VHL
• HDAC

Article highlights

• PanNETs incidence has been gradually increasing over the last two decades and still represents a clinical challenge for physicians

• In the modern oncology era, tailored treatments for PanNETs are limited and no biomarker-guided therapy has ever been approved, despite EVE and SUN being considered targeted agents to some extent

• Strong rationale and preclinical evidence have drawn attention to potential biomarkers to be targeted in the next future, among which we selected the most promising targets: Hsp, HDAC, CDK, HIF, DDR, uPAR

• Key limitations in biomarker-guided therapies development are represented by lack of biomarker stratification, different primary sites inclusion and previous treatments, as well as inadequate endpoint selection

• Targeted agents may influence other treatment efficacy and possibly synergize with them. Therefore, even though biomarker-guided monotherapy may appear unsatisfactory, they may still play a role in combination with other drugs, to enhance their efficacy and overcome primary and secondary resistance

Declaration of interest

N Fazio reports having received from AAA (Advisory board and invited speaker), Novartis (Advisory board), Hutchmed (Advisory board), Merck (Advisory board and invited speaker), and MSD (Advisory board), having received research grants AAA, Merck and Ipsen, having served as local PI of clinical trials for 4SC, Astellas, Beigene, Fibrogen, Incyte, and Ipsen, having served as internal reviewer of NET guidelines for AIOM, having served as a member of the executive committee of ENETS, having served as member of NET faculty of ESMO, and having served as member of the steering committee of SPARC Europe.

The authors have no other 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 the manuscript apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.