Personalized drug screening and risk assessment in patient-derived gastroenteropancreatic neuroendocrine neoplasms

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.