DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms

Abstract

Introduction: Neuroendocrine neoplasms (NEN) are heterogeneous malignancies that can arise at almost any anatomical site and are classified as biologically distinct well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Current systemic therapies for advanced disease, including targeted therapies, chemotherapy, and immunotherapy, are associated with limited duration of response. New therapeutic targets are needed. One promising target is delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch receptor whose overexpression on the surface of NEN is associated with tumorigenesis.

Methods: This article is a narrative review that highlights the role of DLL3 in NEN progression and prognosis, the potential for therapeutic targeting of DLL3, and ongoing studies of DLL3-targeting therapies. Classification, incidence, pathogenesis, and current management of NEN are reviewed to provide biological context and illustrate the unmet clinical needs.

Discussion: DLL3 is overexpressed in many NENs, implicated in tumor progression, and is typically associated with poor clinical outcomes, particularly in patients with NEC. Targeted therapies using DLL3 as a homing beacon for cytotoxic activity mediated via several different mechanisms (eg, antibody-drug conjugates, T-cell engager molecules, CAR-Ts) have shown promising clinical activity in small-cell lung cancer (SCLC). DLL3 may be a clinically actionable target across NEN.

Conclusions: Current treatment options for NEN do not provide sustained responses. DLL3 is expressed on the cell surface of many NEN types and is associated with poor clinical outcomes. Initial clinical studies targeting DLL3 therapeutically in SCLC have been promising, and additional studies are expanding this approach to the broader group of NEN.

Keywords: DLL3 protein; human; molecular targeted therapy; neuroendocrine carcinoma; neuroendocrine tumors.

Figure 1.

Representative DLL3 prevalence (ie, >1% DLL3-expressing cells) by immunohistochemistry in NEN tumors.^,, *Prevalence of high DLL3 expression (ie, ≥50% of DLL3-expressing cells). ^†Strongly positive for DLL3. Abbreviations: Adeno, adenocarcinoma; CRPC, castration-resistant prostate cancer; DLL3, delta-like ligand 3; LCNEC, large-cell neuroendocrine cancer; NEPC, neuroendocrine prostate cancer; NEN, neuroendocrine neoplasms.

Figure 2.

DLL3 immunohistochemical staining by the site of origin, including (A-D) Lung NET (reproduced with permission from Drs Ali, Di Stefano, Poma, Ricci, Proietti, Davini, Lucchi, Melfi, and Fontanini from their original publication in Front Oncol), and (E-F) NEPC. Representative images showing variable percentages of DLL3 immunohistochemical staining in lung NET: (A) typical carcinoid DLL3 negative; (B) a case of atypical carcinoid showing combined cytoplasmic and membranous staining with moderate intensity; (C) Large-cell NEC with strong and diffuse DLL3 staining; (D) high (>50% positive tumor cells) immunohistochemical expression level of DLL3 in a small-cell lung carcinoma specimen (magnification, ×20) using rabbit anti-DLL3 antibody (clone SP347; Ventana Medical Systems, Inc. Tucson, AZ, USA); (E) adenocarcinoma with neuroendocrine component (H-score of 65, 80% positive cells) and (F) NEPC (H-score of 150, 90% positive cells) using rabbit anti-DLL3 antibody (clone SP347).^, Abbreviations: DLL3, delta-like ligand 3; NEC, neuroendocrine carcinoma; NEPC, neuroendocrine prostate cancer; NET, neuroendocrine tumor.