Tyrosine kinase inhibitor therapy and metabolic remodelling in papillary thyroid cancer

in Endocrine-Related Cancer
View More View Less
  • 1 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada
  • 2 Department of Surgery and Surgical Oncology, 2D, Walter C Mackenzie Health Sciences Centre, University of Alberta, Edmonton, Canada

Correspondence should be addressed to F Wuest or T P W McMullen: wuest@ualberta.ca or todd.mcmullen@ualberta.ca

*(M Wagner and M Wuest contributed equally to this work)

Restricted access

Targeted therapy is increasingly used to manage metastatic papillary thyroid cancer. The focus of the present study was to examine glucose metabolism and tumor responses for thyroid cancer xenografts expressing the glycolytic pathway modulators platelet-derived growth factor receptor (PDGFR) and BRAFV600E. Radiolabelled glucose derivative [18F]FDG was used to analyze the effects of PDGFR blockade with imatinib, BRAF blockade with vemurafenib, as well as combined PDGFR and BRAF blockade in vitro and in vivo with PET. Dynamic PET data was correlated with immunohistochemistry staining and kinetic analysis for facilitative glucose transporter 1 (GLUT1) and hexokinase-II (HK2). Vemurafenib decreased [18F]FDG uptake in BCPAP cells in vitro; however, it was increased by ~70% with imatinib application to BCPAP cells. This metabolic response to tyrosine kinase inhibition required BRAFV600E as it was not seen in cell lines lacking mutated BRAF (TPC1). In xenografts, imatinib therapy in BCPAP thyroid tumour-bearing mice significantly increased [18F]FDG uptake and retention (>30%) in BCPAP tumours with PDGFRβ or both (α+β) isoforms. Kinetic analysis revealed that the increased glucose uptake is a consequence of increased phosphorylation and intracellular trapping of [18F]FDG confirmed by an increase in HK2 protein expression and activity, but not GLUT1 activity. BRAF inhibition alone, or combined PDGFR and BRAF inhibition, reduced (~60%) [18F]FDG uptake in both types of BCPAP (β or α+β) tumours. In terms of tumour growth, combination therapy with imatinib and vemurafenib led to a near abolition of the tumors (~90% reduction), but single therapy for BCPAP with PDGFRα expression was much less effective. In summary, imatinib led to a paradoxical increase of [18F]FDG uptake in xenografts that was reversed through BRAFV600E inhibition. The present data show that metabolic reprogramming in thyroid cancer occurs as a consequence of BRAF-mediated upregulation of HK2 expression that may permit tumour growth with isolated blockade of upstream tyrosine kinase receptors.

 

      Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 653 653 137
Full Text Views 32 32 8
PDF Downloads 33 33 9
  • Barrio M, Czernin J, Yeh MW, Palma Diaz MF, Gupta P, Allen-Auerbach M, Schiepers C & Herrmann K 2016 The incidence of thyroid cancer in focal hypermetabolic thyroid lesions: an 18F-FDG PET/CT study in more than 6000 patients. Nuclear Medicine Communications 37 12901296. (https://doi.org/10.1097/MNM.0000000000000592)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ben-David H, Aruna BV, Seger R, Sela M & Mozes E 2006 A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses. PNAS 103 1823218237. (https://doi.org/10.1073/pnas.0608896103)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ciavardelli D, Bellomo M, Consalvo A, Crescimanno C & Vella V 2017 Metabolic alterations of thyroid cancer as potential therapeutic targets. BioMed Research International 2017 2545031. (https://doi.org/10.1155/2017/2545031)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Coelho RG, Cazarin JM, Cavalcanti de Albuquerque JP, de Andrade BM & Carvalho DP 2016 Differential glycolytic profile and Warburg effect in papillary thyroid carcinoma cell lines. Oncology Reports 36 36733681. (https://doi.org/10.3892/or.2016.5142)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, Caillou B, Ricard M, Lumbroso JD, De Vathaire F, 2006 Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. Journal of Clinical Endocrinology and Metabolism 91 28922899. (https://doi.org/10.1210/jc.2005-2838)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ekpe-Adewuyi E, Lopez-Campistrous A, Tang X, Brindley DN & McMullen TP 2016 Platelet derived growth factor receptor alpha mediates nodal metastases in papillary thyroid cancer by driving the epithelial-mesenchymal transition. Oncotarget 7 8368483700. (https://doi.org/10.18632/oncotarget.13299)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Farwell MD, Pryma DA & Mankoff DA 2014 PET/CT imaging in cancer: current applications and future directions. Cancer 120 34333445. (https://doi.org/10.1002/cncr.28860)

  • Faustino-Rocha A, Oliveira PA, Pinho-Oliveira J, Teixeira-Guedes C, Soares-Maia R, da Costa RG, Colaço B, Pires MJ, Colaço J, Ferreira R, 2013 Estimation of rat tumor volume using caliper and ultrasonography measurements. Lab Animal 42 217224. (https://doi.org/10.1038/laban.254)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Feng C, Gao Y, Wang C, Yu X, Zhang W, Guan H, Shan Z & Teng W 2013 Aberrant overexpression of pyruvate kinase M2 is associated with aggressive tumor features and the BRAF mutation in papillary thyroid cancer. Journal of Clinical Endocrinology and Metabolism 98 E1524E1533. (https://doi.org/10.1210/jc.2012-4258)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ferretta A, Maida I, Guida S, Azzariti A, Porcelli L, Tommasi S, Zanna P, Cocco T, Guida M & Guida G 2016 New insight into the role of metabolic reprogramming in melanoma cells harboring BRAF mutations. Biochimica et Biophysica Acta 1863 27102718. (https://doi.org/10.1016/j.bbamcr.2016.08.007)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hamacher K, Coenen HH & Stocklin G 1986 Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-Dglucose using aminopolyether supported nucleophilic substitution. Journal of Nuclear Medicine 27 235238.

    • Search Google Scholar
    • Export Citation
  • Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, 2016 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 26 1133. (https://doi.org/10.1089/thy.2015.0020)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hutton JE, Wang X, Zimmerman LJ, Slebos RJ, Trenary IA, Young JD, Li M & Liebler DC 2016 Oncogenic KRAS and BRAF drive metabolic reprogramming in colorectal cancer. Molecular and Cellular Proteomics 15 29242938. (https://doi.org/10.1074/mcp.M116.058925)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Jans HS, Yang XH, Brooks DR, Kumar P, Wuest M & Wiebe LI 2018 Positron emission tomography (PET) and pharmacokinetics: classical blood sampling versus image-derived analysis of [18F]FAZA and [18F]FDG in a murine tumor bearing model. Journal of Pharmacy and Pharmaceutical Sciences 21 32s47s. (https://doi.org/10.18433/jpps29788)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Klein Hesselink EN, Steenvoorden D, Kapiteijn E, Corssmit EP, van der Horst-Schrivers AN, Lefrandt JD, Links TP & Dekkers OM 2015 Therapy of endocrine disease: response and toxicity of small-molecule tyrosine kinase inhibitors in patients with thyroid carcinoma: a systematic review and meta-analysis. European Journal of Endocrinology 172 R215R225. (https://doi.org/10.1530/EJE-14-0788)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kraeber-Bodéré F, Carlier T, Naegelen VM, Shochat E, Lumbroso J, Trampal C, Nagarajah J, Chua S, Hugonnet F, Stokkel M, 2012 Differences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials. Journal of Nuclear Medicine 53 18361846. (https://doi.org/10.2967/jnumed.112.109421)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lee SH, Han S, Lee HS, Chae SY, Lee JJ, Song DE & Ryu JS 2016 Association between 18F-FDG avidity and the BRAF mutation in papillary thyroid carcinoma. Nuclear Medicine and Molecular Imaging 50 3845. (https://doi.org/10.1007/s13139-015-0367-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu JW, Chen C, Loh EW, Chu CC, Wang MY, Ouyang HJ, Chang YT, Zhuang WZ, Chou CW, Huang DJ, 2018 Tyrosine kinase inhibitors for advanced or metastatic thyroid cancer: a meta-analysis of randomized controlled trials. Current Medical Research and Opinion 34 795803. (https://doi.org/10.1080/03007995.2017.1368466)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lopez-Campistrous A, Adewuyi EE, Benesch MGK, Ko YM, Lai R, Thiesen A, Dewald J, Wang P, Chu K, Ghosh S, 2016 PDGFRα regulates follicular cell differentiation driving treatment resistance and disease recurrence in papillary thyroid cancer. EBioMedicine 12 8697. (https://doi.org/10.1016/j.ebiom.2016.09.007)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ma J, Wu X, Li J, Wang Z & Wang Y 2017 Prognostic value of early response assessment using (18F) FDG-PET in patients with advanced non-small cell lung cancer treated with tyrosine-kinase inhibitors. Journal of Investigative Medicine 65 935941.

    • Search Google Scholar
    • Export Citation
  • Marcus C, Whitworth PW, Surasi DS, Pai SI & Subramaniam RM 2014 PET/CT in the management of thyroid cancers. American Journal of Roentgenology 202 13161329. (https://doi.org/10.2214/AJR.13.11673)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Matrone A, Valerio L, Pieruzzi L, Giani C, Cappagli V, Lorusso L, Agate L, Puleo L, Viola D, Bottici V, 2017 Protein kinase inhibitors for the treatment of advanced and progressive radiorefractory thyroid tumors: from the clinical trials to the real life. Best Practice and Research: Clinical Endocrinology and Metabolism 31 319334. (https://doi.org/10.1016/j.beem.2017.06.001)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nagarajah J, Ho AL, Tuttle RM, Weber WA & Grewal RK 2015 Correlation of BRAFV600E mutation and glucose metabolism in thyroid cancer patients: an ¹8F-FDG PET study. Journal of Nuclear Medicine 56 662667. (https://doi.org/10.2967/jnumed.114.150607)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Parmenter TJ, Kleinschmidt M, Kinross KM, Bond ST, Li J, Kaadige MR, Rao A, Sheppard KE, Hugo W, Pupo GM, 2014 Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discovery 4 423433. (https://doi.org/10.1158/2159-8290.CD-13-0440)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pascal P, Dercle L, Weyts K, Meyer N & Courbon F 2018 Complete metabolic response of advanced melanoma to vemurafenib assessed with FDG-PET-CT at 85 hours. Clinical Nuclear Medicine 43 333334. (https://doi.org/10.1097/RLU.0000000000002032)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Poliaková M, Aebersold DM, Zimmer Y & Medová M 2018 The relevance of tyrosine kinase inhibitors for global metabolic pathways in cancer. Molecular Cancer 17 27. (https://doi.org/10.1186/s12943-018-0798-9)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Prenen H, Deroose C, Vermaelen P, Sciot R, Debiec-Rychter M, Stroobants S, Mortelmans L, Schöffski P & Van Oosterom A 2006 Establishment of a mouse gastrointestinal stromal tumour model and evaluation of response to imatinib by small animal positron emission tomography. Anticancer Research 26 12471252.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ran C, Liu H, Hitoshi Y & Israel MA 2013 Proliferation-independent control of tumor glycolysis by PDGFR-mediated AKT activation. Cancer Research 73 18311843. (https://doi.org/10.1158/0008-5472.CAN-12-2460)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Revheim ME, Røe K, Bruland ØS, Bach-Gansmo T, Skretting A & Seierstad T 2011 Monitoring the effect of targeted therapies in a gastrointestinal stromal tumor xenograft using a clinical PET/CT. Molecular Imaging and Biology 13 12341240. (https://doi.org/10.1007/s11307-010-0464-0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Sabbatino F, Wang Y, Wang X, Flaherty KT, Yu L, Pepin D, Scognamiglio G, Pepe S, Kirkwood JM, Cooper ZA, 2014 PDGFRα up-regulation mediated by Sonic Hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. Oncotarget 5 19261941. (https://doi.org/10.18632/oncotarget.1878)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Santhanam P, Khthir R, Solnes LB & Ladenson PW 2018 The relationship of BRAFV600E mutation status to FDG PET/CT avidity in thyroid cancer: a review and meta-analysis. Endocrine Practice 24 2126. (https://doi.org/10.4158/EP-2017-0080)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Sheikhbahaei S, Mena E, Yanamadala A, Reddy S, Solnes LB, Wachsmann J & Subramaniam RM 2017 The value of FDG PET/CT in treatment response assessment, follow-up, and surveillance of lung cancer. American Journal of Roentgenology 208 420433. (https://doi.org/10.2214/AJR.16.16532)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Takeuchi S, Shiga T, Hirata K, Taguchi J, Magota K, Ariga S, Gouda T, Ohhara Y, Homma R, Shimizu Y, 2018 Early prediction of lenvatinib treatment efficacy by using 18F-FDG PET/CT in patients with unresectable or advanced thyroid carcinoma that is refractory to radioiodine treatment: a protocol for a non-randomized single-arm multicenter observational study. BMJ Open 8 e021001. (https://doi.org/10.1136/bmjopen-2017-021001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thézé B, Bernards N, Beynel A, Bouet S, Kuhnast B, Buvat I, Tavitian B & Boisgard R 2015 Monitoring therapeutic efficacy of sunitinib using [(18)F]FDG and [(18)F]FMISO PET in an immunocompetent model of luminal B (HER2-positive)-type mammary carcinoma. BMC Cancer 15 534. (https://doi.org/10.1186/s12885-015-1540-2)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Treglia G, Mirk P, Stefanelli A, Rufini V, Giordano A & Bonomo L 2012 18F-Fluorodeoxyglucose positron emission tomography in evaluating treatment response to imatinib or other drugs in gastrointestinal stromal tumors: a systematic review. Clinical Imaging 36 167175. (https://doi.org/10.1016/j.clinimag.2011.08.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tseng JC, Narayanan N, Ho G, Groves K, Delaney J, Bao B, Zhang J, Morin J, Kossodo S, Rajopadhye M, 2017 Fluorescence imaging of bombesin and transferrin receptor expression is comparable to 18F-FDG PET in early detection of sorafenib-induced changes in tumor metabolism. PLoS ONE 12 e0182689. (https://doi.org/10.1371/journal.pone.0182689)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ueno D, Yao M, Tateishi U, Minamimoto R, Makiyama K, Hayashi N, Sano F, Murakami T, Kishida T, Miura T, 2012 Early assessment by FDG-PET/CT of patients with advanced renal cell carcinoma treated with tyrosine kinase inhibitors is predictive of disease course. BMC Cancer 12 162. (https://doi.org/10.1186/1471-2407-12-162)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Valerio L, Pieruzzi L, Giani C, Agate L, Bottici V, Lorusso L, Cappagli V, Puleo L, Matrone A, Viola D, 2017 Targeted therapy in thyroid cancer: state of the art. Clinical Oncology 29 316324. (https://doi.org/10.1016/j.clon.2017.02.009)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Van den Abbeele AD, Gatsonis C, de Vries DJ, Melenevsky Y, Szot-Barnes A, Yap JT, Godwin AK, Rink L, Huang M, Blevins M, 2012 ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate for operable malignant gastrointestinal stromal tumor: monitoring with 18F-FDG PET and correlation with genotype and GLUT4 expression. Journal of Nuclear Medicine 53 567574. (https://doi.org/10.2967/jnumed.111.094425)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Van Den Hoff J 2005 Principles of quantitative positron emission tomography. Amino Acids 29 341353. (https://doi.org/10.1007/s00726-005-0215-8)

  • Varghese F, Bukhari AB, Malhotra R & De A 2014 IHC profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS ONE 9 e96801. (https://doi.org/10.1371/journal.pone.0096801)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vercellino L, Bousquet G, Baillet G, Barré E, Mathieu O, Just PA, Desgrandchamps F, Misset JL, Hindié E & Moretti JL 2009 18F-FDG PET/CT imaging for an early assessment of response to sunitinib in metastatic renal carcinoma: preliminary study. Cancer Biotherapy and Radiopharmaceuticals 24 137144. (https://doi.org/10.1089/cbr.2008.0527)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Viola D, Valerio L, Molinaro E, Agate L, Bottici V, Biagini A, Lorusso L, Cappagli V, Pieruzzi L, Giani C, 2016 Treatment of advanced thyroid cancer with targeted therapies: ten years of experience. Endocrine-Related Cancer 23 R185R205. (https://doi.org/10.1530/ERC-15-0555)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vitiello GA, Medina BD, Zeng S, Bowler TG, Zhang JQ, Loo JK, Param NJ, Liu M, Moral AJ, Zhao JN, 2018 Mitochondrial inhibition augments the efficacy of imatinib by resetting the metabolic phenotype of gastrointestinal stromal tumor. Clinical Cancer Research 24 972984. (https://doi.org/10.1158/1078-0432.CCR-17-2697)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wagner M, Wuest M, Hamann I, Lopez-Campistrous A, McMullen TPW & Wuest F 2018 Molecular imaging of platelet-derived growth factor receptor-alpha (PDGFRα) in papillary thyroid cancer using immuno-PET. Nuclear Medicine and Biology 58 5158. (https://doi.org/10.1016/j.nucmedbio.2017.12.005)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wong ANM, McArthur GA, Hofman MS & Hicks RJ 2017 The advantages and challenges of using FDG PET/CT for response assessment in melanoma in the era of targeted agents and immunotherapy. European Journal of Nuclear Medicine and Molecular Imaging 44 6777. (https://doi.org/10.1007/s00259-017-3691-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yang JH, Maciel RMB, Nakabashi CCD, Janovsky CCPS, Padovani RP, Macellaro D, Camacho CP, Osawa A, Wagner J & Biscolla RPM 2017 Clinical utility of 18F-FDG PET/CT in the follow-up of a large cohort of patients with high-risk differentiated thyroid carcinoma. Archives of Endocrinology and Metabolism 61 416425. (https://doi.org/10.1590/2359-3997000000285)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yoon M, Jung SJ, Kim TH, Ha TK, Urm SH, Park JS, Lee SM & Bae SK 2016 Relationships between transporter expression and the status of BRAF V600E mutation and F-18 FDG uptake in papillary thyroid carcinomas. Endocrine Research 41 6469. (https://doi.org/10.3109/07435800.2015.1066803)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation