Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures

in Endocrine-Related Cancer
Authors:
Katharina Wang Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

Search for other papers by Katharina Wang in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-7795-1395
,
Ina Schütze Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

Search for other papers by Ina Schütze in
Current site
Google Scholar
PubMed Close
,
Sebastian Gulde Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

Search for other papers by Sebastian Gulde in
Current site
Google Scholar
PubMed Close
,
Nicole Bechmann Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany

Search for other papers by Nicole Bechmann in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-6932-333X
,
Susan Richter Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Search for other papers by Susan Richter in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-3549-2477
,
Jana Helm Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany

Search for other papers by Jana Helm in
Current site
Google Scholar
PubMed Close
,
Michael Lauseker Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Ludwig Maximilian University of Munich, Munich, Germany

Search for other papers by Michael Lauseker in
Current site
Google Scholar
PubMed Close
,
Julian Maurer Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

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

Search for other papers by Astrid Reul in
Current site
Google Scholar
PubMed Close
,
Gerald Spoettl Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

Search for other papers by Gerald Spoettl in
Current site
Google Scholar
PubMed Close
,
Barbara Klink Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
National Center of Genetics, Laboratoire National de Santé, Dudelange, Luxembourg
German Cancer Consortium, Dresden, Germany

Search for other papers by Barbara Klink in
Current site
Google Scholar
PubMed Close
,
Doreen William German Cancer Consortium, Dresden, Germany

Search for other papers by Doreen William in
Current site
Google Scholar
PubMed Close
,
Thomas Knösel Institute of Pathology, Ludwig Maximilian University of Munich, Munich, Germany

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

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

Search for other papers by Michel Bihl in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-5884-739X
,
Achim Weber Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland

Search for other papers by Achim Weber in
Current site
Google Scholar
PubMed Close
,
Maria Fankhauser Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

Search for other papers by Maria Fankhauser in
Current site
Google Scholar
PubMed Close
,
Laura Schober Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

Search for other papers by Laura Schober in
Current site
Google Scholar
PubMed Close
,
Diana Vetter Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland

Search for other papers by Diana Vetter in
Current site
Google Scholar
PubMed Close
,
Martina Broglie Däppen Department of Otorhinolaryngology, University Hospital Zurich, Zurich, Switzerland

Search for other papers by Martina Broglie Däppen in
Current site
Google Scholar
PubMed Close
,
Christian G Ziegler Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany

Search for other papers by Christian G Ziegler in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-4345-696X
,
Martin Ullrich Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

Search for other papers by Martin Ullrich in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0001-6104-6676
,
Jens Pietzsch Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Dresden, Germany

Search for other papers by Jens Pietzsch in
Current site
Google Scholar
PubMed Close
,
Stefan R Bornstein Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany

Search for other papers by Stefan R Bornstein in
Current site
Google Scholar
PubMed Close
,
Christian Lottspeich Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

Search for other papers by Christian Lottspeich in
Current site
Google Scholar
PubMed Close
,
Matthias Kroiss Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany
Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital Würzburg, University of Würzburg, Würzburg, Germany

Search for other papers by Matthias Kroiss in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-7628-3161
,
Martin Fassnacht Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital Würzburg, University of Würzburg, Würzburg, Germany

Search for other papers by Martin Fassnacht in
Current site
Google Scholar
PubMed Close
,
Vera Ursula Julia Wenter Department of Nuclear Medicine, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

Search for other papers by Vera Ursula Julia Wenter in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0001-7385-5702
,
Roland Ladurner Department of General-, Visceral-, and Transplant-Surgery, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

Search for other papers by Roland Ladurner in
Current site
Google Scholar
PubMed Close
,
Constanze Hantel Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany

Search for other papers by Constanze Hantel in
Current site
Google Scholar
PubMed Close
,
Martin Reincke Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

Search for other papers by Martin Reincke in
Current site
Google Scholar
PubMed Close
,
Graeme Eisenhofer Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany

Search for other papers by Graeme Eisenhofer in
Current site
Google Scholar
PubMed Close
,
Ashley B Grossman Green Templeton College, University of Oxford, Oxford, UK
NET Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK

Search for other papers by Ashley B Grossman in
Current site
Google Scholar
PubMed Close
,
Karel Pacak Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Karel Pacak in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-3541-3767
,
Felix Beuschlein Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany
Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland

Search for other papers by Felix Beuschlein in
Current site
Google Scholar
PubMed Close
,
Christoph J Auernhammer Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany

Search for other papers by Christoph J Auernhammer in
Current site
Google Scholar
PubMed Close
,
Natalia S Pellegata Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

Search for other papers by Natalia S Pellegata in
Current site
Google Scholar
PubMed Close
, and
Svenja Nölting Department of Internal Medicine IV, University Hospital, LMU Klinikum, Ludwig Maximilian University of Munich, Munich, Germany
Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital 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

*(K Wang and I Schütze contributed equally to this work)

DOI:
https://doi.org/10.1530/ERC-21-0355
Volume/Issue:
Volume 29: Issue 6
Article Type:
Research Article
Page Range:
285–306
Online Publication Date:
09 May 2022
Copyright:
© Society for Endocrinology 2022
Restricted access
Rent on DeepDyve

Sign up for journal news

Aggressive pheochromocytomas and paragangliomas (PPGLs) are difficult to treat, and molecular targeting is being increasingly considered, but with variable results. This study investigates established and novel molecular-targeted drugs and chemotherapeutic agents for the treatment of PPGLs in human primary cultures and murine cell line spheroids. In PPGLs from 33 patients, including 7 metastatic PPGLs, we identified germline or somatic driver mutations in 79% of cases, allowing us to assess potential differences in drug responsivity between pseudohypoxia-associated cluster 1-related (n  = 10) and kinase signaling-associated cluster 2-related (n  = 14) PPGL primary cultures. Single anti-cancer drugs were either more effective in cluster 1 (cabozantinib, selpercatinib, and 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, and high-dose zoledronic acid). High-dose estrogen and low-dose zoledronic acid were the only single substances more effective in cluster 2. Neither cluster 1- nor cluster 2-related patient primary cultures responded to HIF-2a inhibitors, temozolomide, dabrafenib, or octreotide. We showed particular efficacy of targeted combination treatments (cabozantinib/everolimus, alpelisib/everolimus, alpelisib/trametinib) in both clusters, with higher efficacy of some targeted combinations in cluster 2 and overall synergistic effects (cabozantinib/everolimus, alpelisib/trametinib) or synergistic effects in cluster 2 (alpelisib/everolimus). Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be promising treatment options with particularly high efficacy in SDHB-mutant and metastatic tumors. In conclusion, only minor differences regarding drug responsivity were found between cluster 1 and cluster 2: some single anti-cancer drugs were more effective in cluster 1 and some targeted combination treatments were more effective in cluster 2.

Supplementary Materials

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 822 125 16
PDF Downloads 751 144 16

 

  • Collapse
  • Expand
Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© Society for Endocrinology 2022
Page(s):
22
Received Date:
01 Mar 2022
Accepted Date:
23 Mar 2022
Print Publication Date:
01 Jun 2022
Online Publication Date:
09 May 2022
Keywords:
personalized drug testing; pheochromocytoma/paraganglioma; human primary cultures; 3D spheroid models; somatic mutations

  • Alzofon N, Koc K, Panwell K, Pozdeyev N, Marshall CB, Albuja-Cruz M, Raeburn CD, Nathanson KL, Cohen DL & Wierman ME et al.2021 Mastermind like transcriptional coactivator 3 (MAML3) drives neuroendocrine tumor progression. Molecular Cancer Research 19 1476–1485. (https://doi.org/10.1158/1541-7786.MCR-20-0992)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • April-Monn SL, Wiedmer T, Skowronska M, Maire R, Schiavo Lena M, Trippel M, Di Domenico A, Muffatti F, Andreasi V & Capurso G et al.2021 Three-dimensional primary cell culture: a novel preclinical model for pancreatic neuroendocrine tumors. Neuroendocrinology 111 273–287. (https://doi.org/10.1159/000507669)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • 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

  • Ayala-Ramirez M, Chougnet CN, Habra MA, Palmer JL, Leboulleux S, Cabanillas ME, Caramella C, Anderson P, Al Ghuzlan A & Waguespack SG et al.2012 Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. Journal of Clinical Endocrinology and Metabolism 97 4040–4050. (https://doi.org/10.1210/jc.2012-2356)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Baudin E, Goichot B, Berruti A, Hadoux J, Moalla S, Laboureau S, Noelting S, Fouchardière CDL, Kienitz T & Deutschbein T et al.2021 First International Randomized Study in malignant progressive pheochromocytoma and paragangliomas (FIRSTMAPPP): an academic double-blind trial investigating sunitinib. Annals of Oncology 32 S621–S625. doi:10.1016/annonc/annonc700.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bayley JP & Devilee P 2020 Advances in paraganglioma-pheochromocytoma cell lines and xenografts. Endocrine-Related Cancer 27 R433–R450. (https://doi.org/10.1530/ERC-19-0434)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bechmann N & Eisenhofer G 2021 Hypoxia-inducible factor 2alpha: a key player in tumorigenesis and metastasis of pheochromocytoma and paraganglioma ? Experimental and Clinical Endocrinology and Diabetes [epub]. (https://doi.org/10.1055/a-1526-5263)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bechmann N, Ehrlich H, Eisenhofer G, Ehrlich A, Meschke S, Ziegler CG & Bornstein SR 2018 Anti-tumorigenic and anti-metastatic activity of the sponge-derived marine drugs aeroplysinin-1 and isofistularin-3 against pheochromocytoma in vitro. Marine Drugs 16 172. (https://doi.org/10.3390/md16050172)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bechmann N, Poser I, Seifert V, Greunke C, Ullrich M, Qin N, Walch A, Peitzsch M, Robledo M & Pacak K et al.2019 Impact of extrinsic and intrinsic hypoxia on catecholamine biosynthesis in absence or presence of Hif2alpha in pheochromocytoma cells. Cancers 11 594. (https://doi.org/10.3390/cancers11050594)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bechmann N, Moskopp ML, Ullrich M, Calsina B, Wallace PW, Richter S, Friedemann M, Langton K, Fliedner SMJ & Timmers HJLM et al.2020 HIF2alpha supports pro-metastatic behavior in pheochromocytomas/paragangliomas. Endocrine-Related Cancer 27 625–640. (https://doi.org/10.1530/ERC-20-0205)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bukowski RM & Vidt DG 1984 Chemotherapy trials in malignant pheochromocytoma: report of two patients and review of the literature. Journal of Surgical Oncology 27 89–92. (https://doi.org/10.1002/jso.2930270207)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Burnichon N, Vescovo L, Amar L, Libé R, De Reynies A, Venisse A, Jouanno E, Laurendeau I, Parfait B & Bertherat J et al.2011 Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Human Molecular Genetics 20 3974–3985. (https://doi.org/10.1093/hmg/ddr324)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Costello BA, Borad MJ, Qi Y, Kim GP, Northfelt DW, Erlichman C & Alberts SR 2014 Phase I trial of everolimus, gemcitabine and cisplatin in patients with solid tumors. Investigational New Drugs 32 710–716. (https://doi.org/10.1007/s10637-014-0096-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Courtney KD, Ma Y, Diaz De Leon A, Christie A, Xie Z, Woolford L, Singla N, Joyce A, Hill H & Madhuranthakam AJ et al.2020 HIF-2 complex dissociation, target inhibition, and acquired resistance with PT2385, a first-in-class HIF-2 inhibitor, in patients with clear cell renal cell carcinoma. Clinical Cancer Research 26 793–803. (https://doi.org/10.1158/1078-0432.CCR-19-1459)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Crona J, Lamarca A, Ghosal S, Welin S, Skogseid B & Pacak K 2019 Genotype-phenotype correlations in pheochromocytoma and paraganglioma: a systematic review and individual patient meta-analysis. Endocrine-Related Cancer 26 539–550. (https://doi.org/10.1530/ERC-19-0024)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Deeks ED 2021 Belzutifan: first approval. Drugs 81 1921–1927. (https://doi.org/10.1007/s40265-021-01606-x)

  • Del Curatolo A, Conciatori F, Cesta Incani U, Bazzichetto C, Falcone I, Corbo V, D’Agosto S, Eramo A, Sette G & Sperduti I et al.2018 Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models. Journal of Experimental and Clinical Cancer Research 37 140. (https://doi.org/10.1186/s13046-018-0820-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Di Ianni N, Maffezzini M, Eoli M & Pellegatta S 2021 Revisiting the immunological aspects of temozolomide considering the genetic landscape and the immune microenvironment composition of glioblastoma. Frontiers in Oncology 11 747690. (https://doi.org/10.3389/fonc.2021.747690)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Druce MR, Kaltsas GA, Fraenkel M, Gross DJ & Grossman AB 2009 Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001). Hormone and Metabolic Research 41 697–702. (https://doi.org/10.1055/s-0029-1220687)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Eisenhofer G, Lenders JW, Siegert G, Bornstein SR, Friberg P, Milosevic D, Mannelli M, Linehan WM, Adams K & Timmers HJ et al.2012 Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. European Journal of Cancer 48 1739–1749. (https://doi.org/10.1016/j.ejca.2011.07.016)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Exner S, Prasad V, Wiedenmann B & Grotzinger C 2018 Octreotide does not inhibit proliferation in five neuroendocrine tumor cell lines. Frontiers in Endocrinology 9 146. (https://doi.org/10.3389/fendo.2018.00146)

    • 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

  • Fassnacht M, Assie G, Baudin E, Eisenhofer G, De La Fouchardiere C, Haak HR, De Krijger R, Porpiglia F, Terzolo M & Berruti A et al.2020 Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 31 1476–1490. (https://doi.org/10.1016/j.annonc.2020.08.2099)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson AG, Johnson AR, Lichtenberg TM, Murray BA, Ghayee HK & Else T et al.2017 Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 31 181–193. (https://doi.org/10.1016/j.ccell.2017.01.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gieldon L, William D, Hackmann K, Jahn W, Jahn A, Wagner J, Rump A, Bechmann N, Nolting S & Knosel T et al.2019 Optimizing genetic workup in pheochromocytoma and paraganglioma by integrating diagnostic and research approaches. Cancers 11 809. (https://doi.org/10.3390/cancers11060809)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Goldstein RE, O’Neill Jr JA, Holcomb 3rd GW, Morgan 3rd WM, Neblett 3rd WW, Oates JA, Brown N, Nadeau J, Smith B & Page DL et al.1999 Clinical experience over 48 years with pheochromocytoma. Annals of Surgery 229 755–764; discussion 764–766. (https://doi.org/10.1097/00000658-199906000-00001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hadoux J, Favier J, Scoazec JY, Leboulleux S, Al Ghuzlan A, Caramella C, Deandreis D, Borget I, Loriot C & Chougnet C et al.2014 SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. International Journal of Cancer 135 2711–2720. (https://doi.org/10.1002/ijc.28913)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hamidi O, Young Jr WF, Gruber L, Smestad J, Yan Q, Ponce OJ, Prokop L, Murad MH & Bancos I 2017 Outcomes of patients with metastatic phaeochromocytoma and paraganglioma: a systematic review and meta-analysis. Clinical Endocrinology 87 440–450. (https://doi.org/10.1111/cen.13434)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hart T, Chandrashekhar M, Aregger M, Steinhart Z, Brown KR, Macleod G, Mis M, Zimmermann M, Fradet-Turcotte A & Sun S et al.2015 High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities. Cell 163 1515–1526. (https://doi.org/10.1016/j.cell.2015.11.015)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Helm J, Drukewitz S, Poser I, Richter S, Friedemann M, William D, Mohr H, Nölting S, Robledo M & Bornstein SR et al.2022 Treatment of pheochromocytoma cells with recurrent cycles of hypoxia: a new pseudohypoxic in vitro model. Cells 11 560. (https://doi.org/10.3390/cells11030560)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Herrera-Martinez AD, Van Den Dungen R, Dogan-Oruc F, Van Koetsveld PM, Culler MD, De Herder WW, Luque RM, Feelders RA & Hofland LJ 2019 Effects of novel somatostatin-dopamine chimeric drugs in 2D and 3D cell culture models of neuroendocrine tumors. Endocrine-Related Cancer 26 585–599. (https://doi.org/10.1530/ERC-19-0086)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hescot S, Curras-Freixes M, Deutschbein T, Van Berkel A, Vezzosi D, Amar L, De La Fouchardiere C, Valdes N, Riccardi F & Do Cao C et al.2019 Prognosis of malignant pheochromocytoma and paraganglioma (MAPP-Prono study): a European network for the study of adrenal tumors retrospective study. Journal of Clinical Endocrinology and Metabolism 104 2367–2374. (https://doi.org/10.1210/jc.2018-01968)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jha A, Patel M, Baker E, Gonzales MK, Ling A, Millo C, Knue M, Civelek AC & Pacak K 2020 Role of 68Ga-DOTATATE PET/CT in a case of SDHB-related pterygopalatine fossa paraganglioma successfully controlled with octreotide. Nuclear Medicine and Molecular Imaging 54 48–52. (https://doi.org/10.1007/s13139-019-00629-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jiang J, Zhang J, Pang Y, Bechmann N, Li M, Monteagudo M, Calsina B, Gimenez-Roqueplo AP, Nolting S & Beuschlein F et al.2020 Sino-European differences in the genetic landscape and clinical presentation of pheochromocytoma and paraganglioma. Journal of Clinical Endocrinology and Metabolism 105 dgaa502. (https://doi.org/10.1210/clinem/dgaa502)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jimenez C, Busaidy N, Habra M, Waguespack S & Jessop A 2017 A phase 2 study to evaluate the effects of cabozantinib in patients with unresectable metastatic pheochromocytomas and paragangliomas. In International Symposium on Pheochromocytoma and Paraganglioma Sydey, Australia.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jin XF, Spoettl G, Maurer J, Nolting S & Auernhammer CJ 2020 Inhibition of Wnt/beta-catenin signaling in neuroendocrine tumors in vitro: antitumoral effects. Cancers 12 345. (https://doi.org/10.3390/cancers12020345)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • John H, Ziegler WH, Hauri D & Jaeger P 1999 Pheochromocytomas: can malignant potential be predicted? Urology 53 679–683. (https://doi.org/10.1016/s0090-4295(9800612-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK & Welsh SJ et al.2021 Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. New England Journal of Medicine 385 2036–2046. (https://doi.org/10.1056/NEJMoa2103425)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Keith B, Johnson RS & Simon MC 2011 HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nature Reviews: Cancer 12 9–22. (https://doi.org/10.1038/nrc3183)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lam AK 2017 Update on adrenal tumours in 2017 World Health Organization (WHO) of endocrine tumours. Endocrine Pathology 28 213–227. (https://doi.org/10.1007/s12022-017-9484-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lenders JWM, Kerstens MN, Amar L, Prejbisz A, Robledo M, Taieb D, Pacak K, Crona J, Zelinka T & Mannelli M et al.2020 Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the working group on endocrine hypertension of the European Society of Hypertension. Journal of Hypertension 38 1443–1456. (https://doi.org/10.1097/HJH.0000000000002438)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li XC, Wu BS, Jiang Y, Li J, Wang ZF, Ma C, Li YR, Yao J, Jin XQ & Li ZQ 2021 Temozolomide-induced changes in gut microbial composition in a mouse model of brain glioma. Drug Design, Development and Therapy 15 1641–1652. (https://doi.org/10.2147/DDDT.S298261)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Long GV, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C & Haydon A et al.2017 Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. New England Journal of Medicine 377 1813–1823. (https://doi.org/10.1056/NEJMoa1708539)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Luchetti A, Walsh D, Rodger F, Clark G, Martin T, Irving R, Sanna M, Yao M, Robledo M & Neumann HP et al.2015 Profiling of somatic mutations in phaeochromocytoma and paraganglioma by targeted next generation sequencing analysis. International Journal of Endocrinology 2015 138573. (https://doi.org/10.1155/2015/138573)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mannelli M, Ianni L, Cilotti A & Conti A 1999 Pheochromocytoma in Italy: a multicentric retrospective study. European Journal of Endocrinology 141 619–624. (https://doi.org/10.1530/eje.0.1410619)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mora J, Cruz O, Parareda A, Sola T & De Torres C 2009 Treatment of disseminated paraganglioma with gemcitabine and docetaxel. Pediatric Blood and Cancer 53 663–665. (https://doi.org/10.1002/pbc.22006)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nölting S, Ullrich M, Pietzsch J, Ziegler CG, Eisenhofer G, Grossman A & Pacak K 2019 Current management of pheochromocytoma/paraganglioma: a guide for the practicing clinician in the era of precision medicine. Cancers 11 1505. (https://doi.org/10.3390/cancers11101505)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nölting S, Bechmann N, Taieb D, Beuschlein F, Fassnacht M, Kroiss M, Eisenhofer G, Grossman A & Pacak K 2022 Personalized management of pheochromocytoma and paraganglioma. Endocrine Reviews 43 199–239. (https://doi.org/10.1210/endrev/bnab019)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Oh DY, Kim TW, Park YS, Shin SJ, Shin SH, Song EK, Lee HJ, Lee KW & Bang YJ 2012 Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas. Cancer 118 6162–6170. (https://doi.org/10.1002/cncr.27675)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • O’Kane GM, Ezzat S, Joshua AM, Bourdeau I, Leibowitz-Amit R, Olney HJ, Krzyzanowska M, Reuther D, Chin S & Wang L et al.2019 A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: the SNIPP trial. British Journal of Cancer 120 1113–1119. (https://doi.org/10.1038/s41416-019-0474-x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pang Y, Lu Y, Caisova V, Liu Y, Bullova P, Huynh TT, Zhou Y, Yu D, Frysak Z & Hartmann I et al.2018 Targeting NAD(+)/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma. Clinical Cancer Research 24 3423–3432. (https://doi.org/10.1158/1078-0432.CCR-17-3406)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Patel M, Tena I, Jha A, Taieb D & Pacak K 2021 Somatostatin receptors and analogs in pheochromocytoma and paraganglioma: old players in a new precision medicine world. Frontiers in Endocrinology 12 625312. (https://doi.org/10.3389/fendo.2021.625312)

    • 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

  • Pham H, Kearns NA & Maehr R 2016 Transcriptional regulation with CRISPR/Cas9 effectors in mammalian cells. Methods in Molecular Biology 1358 43–57. (https://doi.org/10.1007/978-1-4939-3067-8_3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pipas JM & Krywicki RF 2000 Treatment of progressive metastatic glomus jugulare tumor (paraganglioma) with gemcitabine. Neuro-Oncology 2 190–191. (https://doi.org/10.1093/neuonc/2.3.190)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, Souquet PJ, Smit EF, Groen HJ & Kelly RJ et al.2016 Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet: Oncology 17 642–650. (https://doi.org/10.1016/S1470-2045(1600077-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Reid IR, Horne AM, Mihov B, Stewart A, Garratt E, Bastin S & Gamble GD 2020 Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women. Journal of Bone and Mineral Research 35 20–27. (https://doi.org/10.1002/jbmr.3860)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E & Spector E et al.2015 Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine 17 405–424. (https://doi.org/10.1038/gim.2015.30)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rinke A, Auernhammer CJ, Bodei L, Kidd M, Krug S, Lawlor R, Marinoni I, Perren A, Scarpa A & Sorbye H et al.2021 Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine? Gut 70 1768–1781. (https://doi.org/10.1136/gutjnl-2020-321300)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Slinker BK 1998 The statistics of synergism. Journal of Molecular and Cellular Cardiology 30 723–731. (https://doi.org/10.1006/jmcc.1998.0655)

  • Srimuninnimit V & Wampler GL 1991 Case report of metastatic familial pheochromocytoma treated with cisplatin and 5-fluorouracil. Cancer Chemotherapy and Pharmacology 28 217–219. (https://doi.org/10.1007/BF00685513)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tena I, Gupta G, Tajahuerce M, Benavent M, Cifrian M, Falcon A, Fonfria M, Del Olmo M, Reboll R & Conde A et al.2018 Successful second-line metronomic temozolomide in metastatic paraganglioma: case reports and review of the literature. Clinical Medicine Insights. Oncology 12 1179554918763367. (https://doi.org/10.1177/1179554918763367)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tolcher AW, Bendell JC, Papadopoulos KP, Burris 3rd HA, Patnaik A, Jones SF, Rasco D, Cox DS, Durante M & Bellew KM et al.2015 A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors. Annals of Oncology 26 58–64. (https://doi.org/10.1093/annonc/mdu482)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tonyukuk V, Emral R, Temizkan S, Sertcelik A, Erden I & Corapcioglu D 2003 Case report: patient with multiple paragangliomas treated with long acting somatostatin analogue. Endocrine Journal 50 507–513. (https://doi.org/10.1507/endocrj.50.507)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Turkova H, Prodanov T, Maly M, Martucci V, Adams K, Widimsky Jr J, Chen CC, Ling A, Kebebew E & Stratakis CA et al.2016 Characteristics and outcomes of metastatic Sdhb and sporadic pheochromocytoma/paraganglioma: an National Institutes of Health study. Endocrine Practice 22 302–314. (https://doi.org/10.4158/EP15725.OR)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Van den Bossche V, Jadot G, Grisay G, Pierrard J, Honoré N, Petit B, Augusto D, Sauvage S, Laes JF & Seront E 2020 c-MET as a potential resistance mechanism to everolimus in breast cancer: from a case report to patient cohort analysis. Targeted Oncology 15 139–146. (https://doi.org/10.1007/s11523-020-00704-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • van Hulsteijn LT, Van Duinen N, Verbist BM, Jansen JC, Van Der Klaauw AA, Smit JW & Corssmit EP 2013 Effects of octreotide therapy in progressive head and neck paragangliomas: case series. Head and Neck 35 E391–E396. (https://doi.org/10.1002/hed.23348)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang L, Fang D, Xu J & Luo R 2020 Various pathways of zoledronic acid against osteoclasts and bone cancer metastasis: a brief review. BMC Cancer 20 1059. (https://doi.org/10.1186/s12885-020-07568-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Waqar SN, Gopalan PK, Williams K, Devarakonda S & Govindan R 2013 A phase I trial of sunitinib and rapamycin in patients with advanced non-small cell lung cancer. Chemotherapy 59 8–13. (https://doi.org/10.1159/000348584)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wirth LJ, Sherman E, Robinson B, Solomon B, Kang H, Lorch J, Worden F, Brose M, Patel J & Leboulleux S et al.2020 Efficacy of selpercatinib in RET-altered thyroid cancers. New England Journal of Medicine 383 825–835. (https://doi.org/10.1056/NEJMoa2005651)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yaeger R & Corcoran RB 2019 Targeting alterations in the RAF-MEK pathway. Cancer Discovery 9 329–341. (https://doi.org/10.1158/2159-8290.CD-18-1321)

  • 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

  • Zheng L, Gu Y, Silang J, Wang J, Luo F, Zhang B, Li C & Wang F 2021 Prognostic nomograms for predicting overall survival and cancer-specific survival of patients with malignant pheochromocytoma and paraganglioma. Frontiers in Endocrinology 12 684668. (https://doi.org/10.3389/fendo.2021.684668)

    • PubMed
    • Search Google Scholar
    • Export Citation