Personalized Drug Screening and Risk Assessment in Patient-Derived Gastroenteropancreatic Neuroendocrine Neoplasms

CONTEXT: Precision medicine has transformed many areas in oncology. However, it remains largely unexplored in metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), where there is a need for further innovative therapies. OBJECTIVE: To evaluate individual tumor responses to different agents, we have established a standardized personalized drug screening and risk assessment platform using patient-derived GEP-NEN primary cultures (n = 23, 16/23 from metastatic tumors, n = 12 small intestinal neuroendocrine tumors [siNETs], n = 10 pancreatic NETs [pNETs], n = 1 neuroendocrine carcinoma [NEC]). METHODS: We assessed GEP-NEN primary culture cell viability, performed signaling pathway analysis by automated Western blotting and immunohistochemically evaluated tumor composition. RESULTS: Systematic drug testing of 27 agents including signaling inhibitors (i) (mechanistic target of rapamycin inhibitor [mTORi] everolimus, tyrosine kinase inhibitors cabozantinib/sunitinib, AKTi capivasertib, PI3Ki alpelisib, CDK4/6i ribociclib), DNA damage response inhibitors (PARPi niraparib, WEE1i adavosertib, ATRi berzosertib), chemotherapeutics (temozolomide, 5-fluorouracil, lurbinectedin), drug repurposed agents (zoledronic acid), and a personalized risk assessment (glucagon-like peptide [GLP]-2 analogue teduglutide, GLP-1 analogue semaglutide, sex hormones) was performed. We demonstrated statistically significant group effects and individualized responsiveness/resistance data. We identified differences in drug response between pNETs/siNETs and between GEP-NETs/GEP-NEC, respectively. CONCLUSION: We provide novel data on the efficacy of putative and established therapies in patient-derived GEP-NEN primary cultures. Our standardized platform for personalized drug screening and risk assessment in GEP-NEN primary cultures enables prediction of individual tumor treatment response in this orphan disease.