TY - JOUR
T1 - DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms
AU - Yao, James
AU - Bergsland, Emily
AU - Aggarwal, Rahul
AU - Aparicio, Ana
AU - Beltran, Himisha
AU - Crabtree, Judy S.
AU - Hann, Christine L.
AU - Ibrahim, Toni
AU - Byers, Lauren A.
AU - Sasano, Hironobu
AU - Umejiego, John
AU - Pavel, Marianne
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press.
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - DLL3 protein
KW - human
KW - molecular targeted therapy
KW - neuroendocrine carcinoma
KW - neuroendocrine tumors
UR - http://www.scopus.com/inward/record.url?scp=85144026111&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85144026111&partnerID=8YFLogxK
U2 - 10.1093/oncolo/oyac161
DO - 10.1093/oncolo/oyac161
M3 - Article
C2 - 35983951
AN - SCOPUS:85144026111
SN - 1083-7159
VL - 27
SP - 940
EP - 951
JO - Oncologist
JF - Oncologist
IS - 11
ER -