Impact of the PI3K-alpha inhibitor alpelisib on everolimus resistance and somatostatin receptor expression in an orthotopic pancreatic NEC xenograft mouse model

in Endocrine-Related Cancer
Authors:
Ajay-Mohan Mohan Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
Berlin Experimental Radionuclide Imaging Center (BERIC), Charité - Universitätsmedizin Berlin, Berlin, Germany

Search for other papers by Ajay-Mohan Mohan in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0001-7420-6464
,
Sonal Prasad Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
Berlin Experimental Radionuclide Imaging Center (BERIC), Charité - Universitätsmedizin Berlin, Berlin, Germany

Search for other papers by Sonal Prasad in
Current site
Google Scholar
PubMed Close
,
Fabian Schmitz-Peiffer Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
Berlin Experimental Radionuclide Imaging Center (BERIC), Charité - Universitätsmedizin Berlin, Berlin, Germany

Search for other papers by Fabian Schmitz-Peiffer in
Current site
Google Scholar
PubMed Close
,
Catharina Lange Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany

Search for other papers by Catharina Lange in
Current site
Google Scholar
PubMed Close
,
Mathias Lukas Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany

Search for other papers by Mathias Lukas in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-5100-4496
,
Eva J Koziolek Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany

Search for other papers by Eva J Koziolek in
Current site
Google Scholar
PubMed Close
,
Jakob Albrecht Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
Berlin Experimental Radionuclide Imaging Center (BERIC), Charité - Universitätsmedizin Berlin, Berlin, Germany
German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany

Search for other papers by Jakob Albrecht in
Current site
Google Scholar
PubMed Close
,
Daniel Messroghli Department of Internal Medicine - Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany
Preclinical MRI Center, Charité - Universitätsmedizin Berlin, Berlin, Germany

Search for other papers by Daniel Messroghli in
Current site
Google Scholar
PubMed Close
,
Ulrike Stein German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany
Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Translational Oncology of Solid Tumours, Berlin, Germany

Search for other papers by Ulrike Stein in
Current site
Google Scholar
PubMed Close
,
Matthias Ilmer German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany
Department of General, Visceral, and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany
German Cancer Research Center (DKFZ), Heidelberg, Germany

Search for other papers by Matthias Ilmer in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0001-9597-1368
,
Katharina Wang Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany

Search for other papers by Katharina Wang in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-7795-1395
,
Laura Schober Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany

Search for other papers by Laura Schober in
Current site
Google Scholar
PubMed Close
,
Astrid Reul Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital, University of Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

Search for other papers by Astrid Reul in
Current site
Google Scholar
PubMed Close
,
Julian Maurer Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany

Search for other papers by Julian Maurer in
Current site
Google Scholar
PubMed Close
,
Juliane Friemel Department of Pathology and Molecular Pathology, University Zurich and University Hospital Zürich, Zurich, Switzerland

Search for other papers by Juliane Friemel in
Current site
Google Scholar
PubMed Close
,
Achim Weber Department of Pathology and Molecular Pathology, University Zurich and University Hospital Zürich, Zurich, Switzerland

Search for other papers by Achim Weber in
Current site
Google Scholar
PubMed Close
,
Richard A Zuellig Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital, University of Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

Search for other papers by Richard A Zuellig in
Current site
Google Scholar
PubMed Close
,
Constanze Hantel Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany
Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital, University of Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

Search for other papers by Constanze Hantel in
Current site
Google Scholar
PubMed Close
,
Ralph Fritsch Department of Medical Oncology and Hematology, University Zurich and University Hospital Zürich, Zurich, Switzerland

Search for other papers by Ralph Fritsch in
Current site
Google Scholar
PubMed Close
,
Martin Reincke Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany

Search for other papers by Martin Reincke in
Current site
Google Scholar
PubMed Close
,
Karel Pacak Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health (NIH), Bethesda, Maryland, USA

Search for other papers by Karel Pacak in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-3541-3767
,
Ashley B Grossman Green Templeton College, University of Oxford, London, United Kingdom
Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
ENETS Centre of Excellence, Royal Free Hospital, London, United Kingdom

Search for other papers by Ashley B Grossman in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0003-1176-6186
,
Christoph J Auernhammer Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany
ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich, Munich, Germany

Search for other papers by Christoph J Auernhammer in
Current site
Google Scholar
PubMed Close
,
Felix Beuschlein Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital, University of Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

Search for other papers by Felix Beuschlein in
Current site
Google Scholar
PubMed Close
,
Winfried Brenner Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
Berlin Experimental Radionuclide Imaging Center (BERIC), Charité - Universitätsmedizin Berlin, Berlin, Germany
German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany

Search for other papers by Winfried Brenner in
Current site
Google Scholar
PubMed Close
,
Nicola Beindorff Berlin Experimental Radionuclide Imaging Center (BERIC), Charité - Universitätsmedizin Berlin, Berlin, Germany

Search for other papers by Nicola Beindorff in
Current site
Google Scholar
PubMed Close
, and
Svenja Nölting Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany
Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital, University of Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

Search for other papers by Svenja Nölting in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-7064-590X

Correspondence should be addressed to S Nölting: svenja.noelting@usz.ch

*(N Beindorff and S Nölting contributed equally to this work)

DOI:
https://doi.org/10.1530/ERC-23-0041
Volume/Issue:
Volume 31: Issue 1
Article Type:
Research Article
Article ID:
e230041
Online Publication Date:
30 Nov 2023
Copyright:
© the author(s) 2023
Restricted access
Rent on DeepDyve

Sign up for journal news

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.

Endocrine-Related Cancer is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 199 199 11
PDF Downloads 208 208 11

 

  • Collapse
  • Expand
Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© the author(s) 2023
Article ID:
e230041
Received Date:
21 Feb 2023
Accepted Date:
09 Nov 2023
Print Publication Date:
01 Jan 2024
Online Publication Date:
30 Nov 2023
Keywords:
alpelisib; everolimus; pancreatic NEC; pancreatic NET; everolimus resistance

  • Aristizabal Prada ET, Spottl G, Maurer J, Lauseker M, Koziolek EJ, Schrader J, Grossman A, Pacak K, Beuschlein F, Auernhammer CJ, et al.2018 The role of GSK3 and its reversal with GSK3 antagonism in everolimus resistance. Endocrine-Related Cancer 25 893–908. (https://doi.org/10.1530/ERC-18-0159)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bailey D, Chan D, Roach P, Schembri G, Bernard E, Hsiao E, Hayes A, Khasraw M, Samra J & & Pavlakis N 2019 The prognostic impact of dual FDG/somatostatin receptor PET in metastatic neuroendocrine tumours: updated overall survival from the NETPET study. Journal of Nuclear Medicine 60 505.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Beindorff N, Bartelheimer A, Huang K, Lukas M, Lange C, Huang EL, Aschenbach JR, Eary JF, Steffen IG & & Brenner W 2018 Normal values of thyroid uptake of 99mTechnetium pertechnetate SPECT in mice with respect to age, sex, and circadian rhythm. Nuklearmedizin. Nuclear Medicine 57 181–189. (https://doi.org/10.3413/Nukmed-0978-18-05)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bison SM, Pool SE, Koelewijn SJ, van der Graaf LM, Groen HC, Melis M & & de Jong M 2014 Peptide receptor radionuclide therapy (PRRT) with [(177)Lu-DOTA(0),Tyr(3)]octreotate in combination with RAD001 treatment: further investigations on tumor metastasis and response in the rat pancreatic CA20948 tumor model. EJNMMI Research 4 21. (https://doi.org/10.1186/s13550-014-0021-y)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, Cadiot G, Wolin EM, Capdevila J, Wall L, et al.2014 Lanreotide in metastatic enteropancreatic neuroendocrine tumors. New England Journal of Medicine 371 224–233. (https://doi.org/10.1056/NEJMoa1316158)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chan DL, Pavlakis N, Schembri GP, Bernard EJ, Hsiao E, Hayes A, Barnes T, Diakos C, Khasraw M, Samra J, et al.2017 Dual somatostatin receptor/FDG PET/CT imaging in metastatic neuroendocrine tumours: proposal for a novel grading scheme with prognostic significance. Theranostics 7 1149–1158. (https://doi.org/10.7150/thno.18068)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chiara F & & Rasola A 2013 GSK-3 and mitochondria in cancer cells. Frontiers in Oncology 3 16. (https://doi.org/10.3389/fonc.2013.00016)

  • Curigliano G, Martin M, Jhaveri K, Beck JT, Tortora G, Fazio N, Maur M, Hubner RA, Lahner H, Donnet V, et al.2021 Alpelisib in combination with everolimus +/- exemestane in solid tumours: phase Ib randomised, open-label, multicentre study. European Journal of Cancer 151 49–62. (https://doi.org/10.1016/j.ejca.2021.03.042)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Das S & & Dasari A 2021 Epidemiology, incidence, and prevalence of neuroendocrine neoplasms: are there global differences? Current Oncology Reports 23 43. (https://doi.org/10.1007/s11912-021-01029-7)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • de Wilde RF, Edil BH, Hruban RH & & Maitra A 2012 Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy. Nature Reviews Gastroenterology and Hepatology 9 199–208. (https://doi.org/10.1038/nrgastro.2012.9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Djukom C, Porro LJ, Mrazek A, Townsend CM, Hellmich MR & & Chao C 2014 Dual inhibition of PI3K and mTOR signaling pathways decreases human pancreatic neuroendocrine tumor metastatic progression. Pancreas 43 88–92. (https://doi.org/10.1097/MPA.0b013e3182a44ab4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fankhauser M, Bechmann N, Lauseker M, Goncalves J, Favier J, Klink B, William D, Gieldon L, Maurer J, Spottl G, et al.2019 Synergistic highly potent targeted drug combinations in different pheochromocytoma models including human tumor cultures. Endocrinology 160 2600–2617. (https://doi.org/10.1210/en.2019-00410)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • FDA 2019 Highlights of prescribing information. Silver Spring, MD, USA: Food and Drug Administration. (available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212526s000lbl.pdf)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Frilling A, Modlin IM, Kidd M, Russell C, Breitenstein S, Salem R, Kwekkeboom D, Lau WY, Klersy C, Vilgrain V, et al.2014 Recommendations for management of patients with neuroendocrine liver metastases. Lancet. Oncology 15 e8–e21. (https://doi.org/10.1016/S1470-2045(1370362-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hedges CP, Boix J, Jaiswal JK, Shetty B, Shepherd PR & & Merry TL 2021 Efficacy of providing the PI3K p110alpha inhibitor BYL719 (alpelisib) to middle-aged mice in their diet. Biomolecules 11. (https://doi.org/10.3390/biom11020150)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Huang K, Lukas M, Steffen IG, Lange C, Huang EL, Dorau V, Brenner W & & Beindorff N 2018 Normal Values of Renal Function measured with 99mTechnetium mercaptoacetyltriglycine SPECT in Mice with Respect to Age, Sex and Circadian Rhythm. Nuklearmedizin. Nuclear Medicine 57 224–233. (https://doi.org/10.3413/Nukmed-0999-18-09)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jussing E, Milton S, Samen E, Moein MM, Bylund L, Axelsson R, Siikanen J & & Tran TA 2021 Clinically applicable cyclotron-produced gallium-68 gives high-yield radiolabeling of DOTA-based tracers. Biomolecules 11. (https://doi.org/10.3390/biom11081118)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kayani I, Bomanji JB, Groves A, Conway G, Gacinovic S, Win T, Dickson J, Caplin M & & Ell PJ 2008 Functional imaging of neuroendocrine tumors with combined PET/CT using 68ga-DOTATATE (DOTA-DPhe1,Tyr3-octreotate) and 18F-FDG. Cancer 112 2447–2455. (https://doi.org/10.1002/cncr.23469)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kim HJ, Gong MK, Yoon CY, Kang J, Yun M, Cho NH, Rha SY & & Choi YD 2020 Synergistic antitumor effects of combined treatment with HSP90 inhibitor and PI3K/mTOR dual inhibitor in cisplatin-resistant human bladder cancer cells. Yonsei Medical Journal 61 587–596. (https://doi.org/10.3349/ymj.2020.61.7.587)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Launay-Vacher V, Aapro M, de Castro G, Cohen E, Deray G, Dooley M, Humphreys B, Lichtman S, Rey J, Scotte F, et al.2015 Renal effects of molecular targeted therapies in oncology: a review by the Cancer and the Kidney International Network (C-KIN). Annals of Oncology 26 1677–1684. (https://doi.org/10.1093/annonc/mdv136)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu X, Li N, Jiang T, Xu H, Ran Q, Shu Z, Wu J, Li Y, Zhou S & & Zhang B 2020 Comparison of gallium-68 somatostatin receptor and (18)F-fluorodeoxyglucose positron emission tomography in the diagnosis of neuroendocrine tumours: a systematic review and meta-analysis. Hellenic Journal of Nuclear Medicine 23 188–200. (https://doi.org/10.1967/s002449912108)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Markham A 2019 Alpelisib: first global approval. Drugs 79 1249–1253. (https://doi.org/10.1007/s40265-019-01161-6)

  • Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, Washington KM, Carneiro F, Cree IA & Board Whocote 2020 The 2019 WHO classification of tumours of the digestive system. Histopathology 76 182–188. (https://doi.org/10.1111/his.13975)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nölting S, Rentsch J, Freitag H, Detjen K, Briest F, Mobs M, Weissmann V, Siegmund B, Auernhammer CJ, Aristizabal Prada ET, et al.2017 The selective PI3Kalpha inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: results from multiple cell line models. PLoS One 12 e0182852. (https://doi.org/10.1371/journal.pone.0182852)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Okuyama H, Ikeda M, Okusaka T, Furukawa M, Ohkawa S, Hosokawa A, Kojima Y, Hara H, Murohisa G, Shioji K, et al.2020 A Phase II trial of everolimus in patients with advanced pancreatic neuroendocrine carcinoma refractory or intolerant to platinum-containing chemotherapy (NECTOR trial). Neuroendocrinology 110 988–993. (https://doi.org/10.1159/000505550)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Panzuto F, Rinzivillo M, Spada F, Antonuzzo L, Ibrahim T, Campana D, Fazio N & & Delle Fave G 2017 Everolimus in pancreatic neuroendocrine carcinomas G3. Pancreas 46 302–305. (https://doi.org/10.1097/MPA.0000000000000762)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Papadopoli D, Pollak M & & Topisirovic I 2021 The role of GSK3 in metabolic pathway perturbations in cancer. Biochimica et Biophysica Acta. Molecular Cell Research 1868 119059. (https://doi.org/10.1016/j.bbamcr.2021.119059)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Passacantilli I, Capurso G, Archibugi L, Calabretta S, Caldarola S, Loreni F, Delle Fave G & & Sette C 2014 Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition. Oncotarget 5 5381–5391. (https://doi.org/10.18632/oncotarget.2111)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pavel M, Oberg K, Falconi M, Krenning EP, Sundin A, Perren A, Berruti A & ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org 2020 Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 31 844–860. (https://doi.org/10.1016/j.annonc.2020.03.304)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pelicano H, Zhang W, Liu J, Hammoudi N, Dai J, Xu RH, Pusztai L & & Huang P 2014 Mitochondrial dysfunction in some triple-negative breast cancer cell lines: role of mTOR pathway and therapeutic potential. Breast Cancer Research 16 434. (https://doi.org/10.1186/s13058-014-0434-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pool SE, Bison S, Koelewijn SJ, van der Graaf LM, Melis M, Krenning EP & & de Jong M 2013 mTOR inhibitor RAD001 promotes metastasis in a rat model of pancreatic neuroendocrine cancer. Cancer Research 73 12–18. (https://doi.org/10.1158/0008-5472.CAN-11-2089)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, et al.2011 Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. New England Journal of Medicine 364 501–513. (https://doi.org/10.1056/NEJMoa1003825)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, Busam KJ, de Krijger RR, Dietel M, El-Naggar AK, et al.2018 A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Modern Pathology 31 1770–1786. (https://doi.org/10.1038/s41379-018-0110-y)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LAA, Ezzat S, De Herder WW, Klimstra DS, Papotti M, et al.2022 Overview of the 2022 WHO classification of neuroendocrine neoplasms. Endocrine Pathology 33 115–154. (https://doi.org/10.1007/s12022-022-09708-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Blaker M, et al.2009 Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. Journal of Clinical Oncology 27 4656–4663. (https://doi.org/10.1200/JCO.2009.22.8510)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sciammarella C, Luce A, Riccardi F, Mocerino C, Modica R, Berretta M, Misso G, Cossu AM, Colao A, Vitale G, et al.2020 Lanreotide induces cytokine modulation in intestinal neuroendocrine tumors and overcomes resistance to everolimus. Frontiers in Oncology 10 1047. (https://doi.org/10.3389/fonc.2020.01047)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, et al.2021 (177)Lu-Dotatate plus long-acting octreotide versus highdose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncology 22 1752–1763.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vandamme T, Beyens M, de Beeck KO, Dogan F, van Koetsveld PM, Pauwels P, Mortier G, Vangestel C, de Herder W, Van Camp G, et al.2016 Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors. British Journal of Cancer 114 650–658. (https://doi.org/10.1038/bjc.2016.25)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vitali E, Boemi I, Tarantola G, Piccini S, Zerbi A, Veronesi G, Baldelli R, Mazziotti G, Smiroldo V, Lavezzi E, et al.2020 Metformin and everolimus: a promising combination for neuroendocrine tumors treatment. Cancers (Basel) 12. (https://doi.org/10.3390/cancers12082143)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang K, Schutze I, Gulde S, Bechmann N, Richter S, Helm J, Lauseker M, Maurer J, Reul A, Spoettl G, et al.2022 Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures. Endocrine-Related Cancer 29 285–306. (https://doi.org/10.1530/ERC-21-0355)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • White BE, Rous B, Chandrakumaran K, Wong K, Bouvier C, van Hemelrijck M, George G, Russell B, Srirajaskanthan R & & Ramage JK 2022 Incidence and survival of neuroendocrine neoplasia in England 1995–2018: a retrospective, population-based study. Lancet Regional Health. Europe 23 100510. (https://doi.org/10.1016/j.lanepe.2022.100510)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yang S, Xiao X, Meng X & & Leslie KK 2011 A mechanism for synergy with combined mTOR and PI3 kinase inhibitors. PLoS One 6 e26343. (https://doi.org/10.1371/journal.pone.0026343)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yang K, Chen Z, Gao J, Shi W, Li L, Jiang S, Hu H, Liu Z, Xu D & & Wu L 2017 The key roles of GSK-3beta in regulating mitochondrial activity. Cellular Physiology and Biochemistry 44 1445–1459. (https://doi.org/10.1159/000485580)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, et al.2011 Everolimus for advanced pancreatic neuroendocrine tumors. New England Journal of Medicine 364 514–523. (https://doi.org/10.1056/NEJMoa1009290)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, et al.2016 Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387 968–977. (https://doi.org/10.1016/S0140-6736(1500817-X)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yu J, Cao F, Zhao X, Xie Q, Lu M, Li J, Yang Z & & Sun Y 2022 Correlation and comparison of somatostatin receptor Type 2 immunohistochemical scoring systems with 68ga-DOTATATE positron emission tomography/computed tomography imaging in gastroenteropancreatic neuroendocrine neoplasms. Neuroendocrinology 112 358–369. (https://doi.org/10.1159/000517530)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zitzmann K, Ruden J, Brand S, Goke B, Lichtl J, Spottl G & & Auernhammer CJ 2010 Compensatory activation of Akt in response to mTOR and Raf inhibitors - a rationale for dual-targeted therapy approaches in neuroendocrine tumor disease. Cancer Letters 295 100–109. (https://doi.org/10.1016/j.canlet.2010.02.018)

    • PubMed
    • Search Google Scholar
    • Export Citation