Impact of the PI3Kalpha inhibitor alpelisib on everolimus resistance and somatostatin receptor expression in an orthotopic pancreatic NEC xenograft mouse model

Item Type:	Article
Title:	Impact of the PI3Kalpha inhibitor alpelisib on everolimus resistance and somatostatin receptor expression in an orthotopic pancreatic NEC xenograft mouse model
Creators Name:	Mohan, A.M. and Prasad, S. and Schmitz-Peiffer, F. and Lange, C. and Lukas, M. and Koziolek, E.J. and Albrecht, J. and Messroghli, D. and Stein, U. and Ilmer, M. and Wang, K. and Schober, L. and Reul, A. and Maurer, J. and Friemel, J. and Weber, A. and Zuellig, R.A. and Hantel, C. and Fritsch, R. and Reincke, M. and Pacak, K. and Grossman, A.B. and Auernhammer, C.J. and Beuschlein, F. and Brenner, W. and Beindorff, N. and Nölting, S.
Abstract:	The 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 one year. Our aim was to overcome resistance to everolimus by additional treatment with the PI3Kalpha 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 4 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 d), compared to placebo-treated everolimus-resistant tumours (60 d). Within the everolimus-sensitive group, the combination-treated mice showed the longest median survival (52 d). Of all groups, the everolimus-resistant combination-treated group survived longest (69 d). Combination treatment with everolimus and alpelisib seems promising to overcome everolimus resistance in neuroendocrine neoplasms, and should be further examined in a clinical trial.
Keywords:	Everolimus, Heterografts, Neuroendocrine Tumors, Pancreatic Neoplasms, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Positron Emission Tomography Computed Tomography, SCID Mice, Somatostatin Receptors, Animals, Mice
Source:	Endocrine-Related Cancer
ISSN:	1351-0088
Publisher:	HighWire Press
Volume:	31
Number:	1
Page Range:	e230041
Date:	January 2024
Official Publication:	https://doi.org/10.1530/ERC-23-0041
PubMed:	View item in PubMed

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