Study establishing a personalized drug screening platform using patient-derived primary cultures from metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), including testing of GLP-1R-expressing neuroendocrine tumors from small intestinal and pancreatic NETs. Evaluates individual tumor responses to therapeutic agents. Provides a precision oncology tool for evaluating drug sensitivity in GEP-NENs—relevant for understanding GLP-1R expression in neuroendocrine tissues and the theoretical risk of GLP-1 RA effects on neuroendocrine tumor biology.
Abstract
BACKGROUND: 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.
METHODS: To evaluate individual tumor responses to different agents, we have established a standardized personalized drug screening and risk assessment platform utilizing 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]). We assessed 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) (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 (GLP-2 analog teduglutide, GLP-1 analog semaglutide, sex hormones) was performed. We demonstrated significant group effects and individualized responsiveness/resistance data. We identified differences in drug response between pNETs/siNETs and between GEP-NETs/GEP-NEC, respectively.
CONCLUSIONS: 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.