Impact of the PI3K-alpha inhibitor alpelisib on everolimus resistance and somatostatin receptor expression in an orthotopic pancreatic NEC xenograft mouse model
Year: 2023
Type: article
Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) inhibitor everolimus is one of the few approved therapies for locally advanced and metastatic neuroendocrine tumours (NETs). However, after initial disease stabilisation, most patients develop resistance within 1 year. Our aim was to overcome resistance to everolimus by additional treatment with the PI3K-alpha inhibitor alpelisib in an everolimus-resistant orthotopic pancreatic neuroendocrine carcinoma xenograft mouse model. Female SCID mice underwent laparoscopic pancreatic transplantation of everolimus-sensitive (BON1KDMSO) or everolimus-resistant (BON1RR2) NET cells. Both groups were further divided into four treatment groups: placebo, everolimus, alpelisib, and everolimus + alpelisib (combination). Oral treatment was started at a tumour volume of approximately 140 mm3 and continued until 1900-2000 mm3, validated by weekly MRI. Somatostatin receptor expression and tumour viability were analysed by 68Ga-DOTATOC and 18F-FDG PET/CT. Everolimus resistance of the BON1RR2 tumours was confirmed. In the everolimus-sensitive group, everolimus alone, alpelisib alone, and combination treatment significantly prolonged survival, compared to placebo, while in the BON1RR2 group, only combination treatment significantly prolonged survival compared to placebo, but neither everolimus nor alpelisib alone. Placebo-treated everolimus-sensitive tumours grew more rapidly (median survival 45 days), compared to placebo-treated everolimus-resistant tumours (60 days). Within the everolimus-sensitive group, the combination-treated mice showed the longest median survival (52 days). Of all groups, the everolimus-resistant combination-treated group survived longest (69 days). Combination treatment with everolimus and alpelisib seems promising to overcome everolimus resistance in neuroendocrine neoplasms, and should be further examined in a clinical trial.
Source: Endocrine Related Cancer
DOI: 10.1530/erc-23-0041
Authors: Ajay-Mohan Mohan, Sonal Prasad, Fabian Schmitz-Peiffer, Catharina Lange, Mathias Lukas, Eva J Koziolek, Jakob Albrecht, Daniel Messroghli, Ulrike Stein, Matthias Ilmer, Katharina Wang, Laura Schober, Astrid Reul, Julian Maurer, Juliane Friemel, Achim Weber, Richard A Zuellig, Constanze Hantel, Ralph Fritsch, Martin Reincke, Karel Pacak, Ashley B Grossman, Christoph J Auernhammer, Felix Beuschlein, Winfried Brenner, Nicola Beindorff, Svenja Nölting
Institutions: Charité - Universitätsmedizin Berlin, Deutsches Konsortium für Translationale Krebsforschung, Deutsches Herzzentrum der Charité, Max Delbrück Center, German Cancer Research Center, LMU Klinikum, Ludwig-Maximilians-Universität München, University of Zurich, University Hospital Zurich, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Queen Mary University of London, The Royal Free Hospital, University of Oxford
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4388540673