胃肠胰神经内分泌肿瘤中Delta样配体3的表达及功能成像

Delta-like ligand 3 expression and functional imaging in gastroenteropancreatic neuroendocrine neoplasms.

作者信息

Thummalapalli Rohit, Tendler Salomon, Chou Joanne F, Tarcan Zeynep C, Porfido Courtney, Willner Jonathan, Linkov Irina, Bhanot Umesh, Cooper Alissa J, Xu Jierui, Harding James J, Rekhtman Natasha, Tang Laura H, Rudin Charles M, Janjigian Yelena Y, Schöder Heiko, Porier John T, Shia Jinru, Basturk Olca, Reidy-Lagunes Diane, Capanu Marinela, Lewis Jason S, Bodei Lisa, Dunphy Mark P, Raj Nitya

机构信息

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

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.

出版信息

medRxiv. 2025 Jun 25:2025.06.24.25330227. doi: 10.1101/2025.06.24.25330227.

DOI:10.1101/2025.06.24.25330227

PMID:40666328

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12262743/

Abstract

PURPOSE

Delta-like ligand 3 (DLL3) is an emerging target across neuroendocrine cancers, but remains underexplored in gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) including poorly differentiated neuroendocrine carcinomas (GEP NECs) and well differentiated neuroendocrine tumors (NETs). We aimed to define the landscape of DLL3 expression and feasibility of DLL3-targeted imaging in this population.

PATIENTS AND METHODS

We completed DLL3 immunohistochemistry (IHC) on 360 tumor samples from patients with GEP NENs, analyzing associations between DLL3 IHC positivity and clinicopathologic features and outcomes. [Zr]Zr-DFO-SC16.56 DLL3 immunoPET-CT imaging was performed in six patients with DLL3 IHC-positive advanced GEP NENs as part of a phase II clinical trial.

RESULTS

Among GEP NECs, DLL3 expression was identified in 53/75 (71%) samples, was enriched for small cell histology, and did not demonstrate prognostic significance. Among well differentiated pancreatic NETs (PanNETs), DLL3 expression was identified in 22/51 (43%) grade 3 (G3) tumors, with univariate analysis revealing increased mortality risk among patients with DLL3-positive advanced G3 PanNETs (hazard ratio 3.27, 95% confidence interval 1.09-9.78). Between May 28, 2024 and February 10, 2025, six patients with DLL3 IHC-positive GEP NENs were enrolled onto the imaging protocol. [Zr]Zr-DFO-SC16.56 immunoPET-CT imaging delineated DLL3-avid tumor lesions in five of six patients (two of two GEP NECs, three of four G3 PanNETs). Tumor-specific uptake of [Zr]Zr-DFO-SC16.56 varied between patients, with maximum standard uptake values ranging from 7.4-36.7, with four of six cases demonstrating DLL3 avidity in ≥ 50% of tumor lesions.

CONCLUSION

DLL3 is expressed on a majority of GEP NECs and on a subset of high grade PanNETs marked by poor outcomes. Functional imaging suggests DLL3 as a promising therapeutic target in both GEP NECs and high grade PanNETs.

摘要

目的

Delta样配体3（DLL3）是神经内分泌癌中一个新出现的靶点，但在胃肠胰神经内分泌肿瘤（GEP NENs）中仍未得到充分研究，包括低分化神经内分泌癌（GEP NECs）和高分化神经内分泌肿瘤（NETs）。我们旨在明确该人群中DLL3的表达情况以及DLL3靶向成像的可行性。

患者与方法

我们对360例GEP NENs患者的肿瘤样本进行了DLL3免疫组织化学（IHC）检测，分析DLL3 IHC阳性与临床病理特征及预后之间的关联。作为一项II期临床试验的一部分，对6例DLL3 IHC阳性的晚期GEP NENs患者进行了[Zr]Zr-DFO-SC16.56 DLL3免疫正电子发射断层扫描-计算机断层扫描（immunoPET-CT）成像。

结果

在GEP NECs中，75例样本中有53例（71%）检测到DLL3表达，以小细胞组织学为主，且未显示出预后意义。在高分化胰腺NETs（PanNETs）中，51例3级（G3）肿瘤中有22例（43%）检测到DLL3表达，单因素分析显示DLL3阳性的晚期G3 PanNETs患者死亡风险增加（风险比3.27，95%置信区间1.09-9.78）。在2024年5月28日至2025年2月10日期间，6例DLL3 IHC阳性的GEP NENs患者纳入成像方案。[Zr]Zr-DFO-SC16.56 immunoPET-CT成像在6例患者中的5例（2例GEP NECs中的2例，4例G3 PanNETs中的3例）中勾勒出DLL3摄取阳性的肿瘤病灶。[Zr]Zr-DFO-SC16.56的肿瘤特异性摄取在患者之间有所不同，最大标准摄取值范围为7.4-36.7，6例中有4例在≥50%的肿瘤病灶中显示出DLL3摄取阳性。