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

Abstract

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. 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. 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. 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.