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

This study highlights the potential for personalized drug screening in gastroenteropancreatic neuroendocrine neoplasms, although the clinical implications of the findings require further investigation.

Summary and findings

This study evaluated individual tumor responses to various agents using patient-derived gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) primary cultures. A total of 23 samples were analyzed, including 12 small intestinal neuroendocrine tumors and 10 pancreatic NETs. The study aimed to assess drug efficacy and individualized responsiveness using a standardized screening platform.

Abstract

<h4>Context</h4>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.<h4>Objective</h4>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]).<h4>Methods</h4>We assessed GEP-NEN primary culture cell viability, performed signaling pathway analysis by automated Western blotting and immunohistochemically evaluated tumor composition.<h4>Results</h4>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.<h4>Conclusion</h4>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.

Limitations

Not reported in abstract.

Elsewhere in the Teduglutide corpus