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Delta-Like Ligand 3 Expression and Functional Imaging in Gastroenteropancreatic Neuroendocrine Neoplasms

Rohit Thummalapalli1, Salomon Tendler1, Joanne F Chou2

  • 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

JCO Precision Oncology
|November 20, 2025
PubMed
Abstract

Insights

Delta-like ligand 3 (DLL3) is expressed in most gastroenteropancreatic neuroendocrine carcinomas (GEP NECs) and some high-grade pancreatic neuroendocrine tumors (PanNETs). DLL3-targeted imaging shows promise for these neuroendocrine cancer types.

Area of Science:

  • Oncology
  • Molecular Imaging
  • Cancer Biology

Background:

  • Delta-like ligand 3 (DLL3) is a novel target in neuroendocrine cancers.
  • DLL3 expression is not well-characterized in gastroenteropancreatic neuroendocrine neoplasms (GEP NENs).

Purpose of the Study:

  • To investigate DLL3 expression across gastroenteropancreatic neuroendocrine neoplasms (GEP NENs).
  • To assess the feasibility of DLL3-targeted immuno-PET-CT imaging in GEP NENs.

Main Methods:

  • DLL3 immunohistochemistry (IHC) was performed on 379 GEP NEN tumor samples.
  • [89Zr]Zr-DFO-SC16.56 immuno-PET-CT imaging was conducted in six patients with DLL3-positive GEP NENs.

Main Results:

  • DLL3 expression was found in 71% of GEP neuroendocrine carcinomas (NECs) and 40% of grade 3 gastroenteropancreatic neuroendocrine tumors (GEP NETs).
  • DLL3 positivity correlated with increased mortality in advanced G3 PanNETs.
  • Immuno-PET-CT successfully visualized DLL3-avid lesions in 5/6 patients, including GEP NECs and G3 PanNETs.

Conclusions:

  • DLL3 is expressed in a majority of GEP NECs and a subset of high-grade PanNETs.
  • DLL3-targeted imaging demonstrates potential for GEP NECs and high-grade PanNETs.
  • DLL3 represents a promising therapeutic target for these GEP NEN subtypes.

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