Abstract 2157: Feasibility and challenges of developing PDX models of neuroendocrine cancers.

Abstract Neuroendocrine neoplasms (NENs) are a family of heterogenous cancers with neuronal and hormone-secreting features. NENs are subdivided into slow growing well-differentiated neuroendocrine tumors (NETs) and rapidly growing poorly differentiated neuroendocrine carcinomas (NECs). The incidence and prevalence of NENs have been steadily rising over the last twenty years. Yet, few effective therapeutic options are available for curing these complex diseases. The main bottleneck has been linked to the lack of preclinical NEN models for therapy testing. Recent advances in NET patient-derived organoid or spheroid models have significantly improved and contributed to accelerating the drug discovery pipeline. In addition, efforts in developing patient-derived xenograft (PDX) models of NECs have also been successfully reported by several research groups. However, efforts to develop PDX models of NETs remained largely unsuccessful. Our group aimed to prioritize the development of novel NET PDX models. We performed subcutaneous implantation of tumor cells isolated from 50 patient tumor samples from small bowel and pancreatic NETs (sbNETs and pNETs) in NOD scid IL2R gamma null (NSG) mice. Nine engraftments produced detectable tumors within 3-6 months. Of these, 2 sets of mice harbored spontaneously developed mouse tumors with no neuroendocrine feature, and 7 sets of mice harbored human tumor samples confirmed by short tandem repeat analyses to match with the original patient NET samples. Six of the 7 PDX tumors measured less than 5 mm in diameter at 4-6 months post-tumor cell implantation. Although these tumors were small, they recapitulated NET features and expressed NET markers such as synaptophysin (SYP), chromogranin A (CgA), or somatostatin receptor 2 (SSTR2), and have Ki67 staining in less than 25% of the tumor cells. One pNET PDX model yielded large tumors measuring over 10 mm in diameter at 3 months post-tumor cell implantation. Interestingly, these large tumors stained negative for SYP, CgA, or SSTR2, and displayed elevated Ki67 levels (over 35%). Analyses of the mutational landscape of these PDX models are underway and will reveal insights into key genetic regulators that hinder the development of NET PDX models. Overall, these findings highlight both the feasibility and challenges of developing NET PDX. Citation Format: Caleb A. Morgan, Alexandria A. Peterson, Carlos H.F. Chan, Andrew M. Bellizzi, James R. Howe, Po H. Ear. Feasibility and challenges of developing PDX models of neuroendocrine cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2157.