Top

Published in:

Open Access 01-12-2014 | Original research

Synergism of peptide receptor-targeted Auger electron radiation therapy with anti-angiogenic compounds in a mouse model of neuroendocrine tumors

Authors: Andreas Wicki, Damian Wild, Vincent Prêtre, Rosalba Mansi, Annette Orleth, Jean-Claude Reubi, Christoph Rochlitz, Christoph Mamot, Helmut R Mäcke, Gerhard Christofori

Published in: EJNMMI Research | Issue 1/2014

Abstract

Background

Neuroendocrine tumors are well vascularized and express specific cell surface markers, such as somatostatin receptors and the glucagon-like peptide-1 receptor (GLP-1R). Using the Rip1Tag2 transgenic mouse model of pancreatic neuroendocrine tumors (pNET), we have investigated the potential benefit of a combination of anti-angiogenic treatment with targeted internal radiotherapy.

Methods

[Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-exendin-4, a radiopeptide that selectively binds to GLP-1R expressed on insulinoma and other neuroendocrine tumor cells, was co-administered with oral vatalanib (an inhibitor of vascular endothelial growth factor receptors (VEGFR)) or imatinib (a c-kit/PDGFR inhibitor). The control groups included single-agent kinase inhibitor treatments and [Lys⁴⁰(Ahx-DTPA-^natIn)NH₂]-exendin-4 monotherapy. For biodistribution, Rip1Tag2 mice were pre-treated with oral vatalanib or imatinib for 0, 3, 5, or 7 days at a dose of 100 mg/kg. Subsequently, [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-exendin-4 was administered i.v., and the biodistribution was assessed after 4 h. For therapy, the mice were injected with 1.1 MBq [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-exendin-4 and treated with vatalanib or imatinib 100 mg/kg orally for another 7 days. Tumor volume, tumor cell apoptosis and proliferation, and microvessel density were quantified.

Results

Combination of [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-exendin-4 and vatalanib was significantly more effective than single treatments (p < 0.05) and reduced the tumor volume by 97% in the absence of organ damage. The pre-treatment of mice with vatalanib led to a reduction in the tumor uptake of [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-exendin-4, indicating that concomitant administration of vatalanib and the radiopeptide was the best approach. Imatinib did not show a synergistic effect with [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-exendin-4.

Conclusion

The combination of 1.1 MBq of [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-exendin-4 with 100 mg/kg vatalanib had the same effect on a neuroendocrine tumor as the injection of 28 MBq of the radiopeptide alone but without any apparent side effects, such as radiation damage of the kidneys.

Available only for authorised users

Reubi JC, Waser B: Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging 2003, 30: 781–793. 10.1007/s00259-003-1184-3CrossRefPubMed

Reubi JC: Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev 2003, 24: 389–427. 10.1210/er.2002-0007CrossRefPubMed

Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, Feelders RA, van Aken MO, Krenning EP: Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0, Tyr3] octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008, 26: 2124–2130. 10.1200/JCO.2007.15.2553CrossRefPubMed

Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, Mäcke HR, Rochlitz C, Müller-Brand J, Walter MA: Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol 2011, 29: 2416–2423. 10.1200/JCO.2010.33.7873CrossRefPubMed

Korner M, Stockli M, Waser B, Reubi JC: GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 2007, 48: 736–743. 10.2967/jnumed.106.038679CrossRefPubMed

Wicki A, Wild D, Storch D, Seemayer C, Gotthardt M, Behe M, Kneifel S, Mihatsch MJ, Reubi JC, Mäcke HR, Christofori G: [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 is a highly efficient radiotherapeutic for glucagon-like peptide-1 receptor-targeted therapy for insulinoma. Clin Cancer Res 2007, 13: 3696–3705. 10.1158/1078-0432.CCR-06-2965CrossRefPubMed

Wild D, Behe M, Wicki A, Storch D, Waser B, Gotthardt M, Keil B, Christofori G, Reubi JC, Mäcke HR: [Lys40(Ahx-DTPA-¹¹¹In)NH₂]exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting. J Nucl Med 2006, 47: 2025–2033.PubMed

Wild D, Macke H, Christ E, Gloor B, Reubi JC: Glucagon-like peptide 1-receptor scans to localize occult insulinomas. N Engl J Med 2008, 359: 766–768. 10.1056/NEJMc0802045CrossRefPubMed

Turner HE, Harris AL, Melmed S, Wass JA: Angiogenesis in endocrine tumors. Endocr Rev 2003, 24: 600–632. 10.1210/er.2002-0008CrossRefPubMed

10.

Christofori G, Naik P, Hanahan D: Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets and throughout islet cell tumorigenesis. Mol Endocrinol 1995, 9: 1760–1770.PubMed

11.

Casanovas O, Hicklin DJ, Bergers G, Hanahan D: Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005, 8: 299–309. 10.1016/j.ccr.2005.09.005CrossRefPubMed

12.

Mancuso MR, Davis R, Norberg SM, O'Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu-Lowe DD, McDonald DM: Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 2006, 116: 2610–2621. 10.1172/JCI24612PubMedCentralCrossRefPubMed

13.

Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O: Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009, 15: 220–231. 10.1016/j.ccr.2009.01.027PubMedCentralCrossRefPubMed

14.

Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, Rubin K: Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 2001, 61: 2929–2934.PubMed

15.

Baranowska-Kortylewicz J, Abe M, Pietras K, Kortylewicz ZP, Kurizaki T, Nearman J, Paulsson J, Mosley RL, Enke CA, Ostman A: Effect of platelet-derived growth factor receptor-beta inhibition with STI571 on radioimmunotherapy. Cancer Res 2005, 65: 7824–7831.PubMedCentralPubMed

16.

Jain RK: Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005, 307: 58–62. 10.1126/science.1104819CrossRefPubMed

17.

Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, de Bruijn EA, van Oosterom AT: Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer 2003, 88: 1979–1986. 10.1038/sj.bjc.6601005PubMedCentralCrossRefPubMed

18.

Scott EN, Meinhardt G, Jacques C, Laurent D, Thomas AL: Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours. Expert Opin Investig Drugs 2007, 16: 367–379. 10.1517/13543784.16.3.367CrossRefPubMed

19.

Song S, Ewald AJ, Stallcup W, Werb Z, Bergers G: PDGFRbeta + perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 2005, 7: 870–879. 10.1038/ncb1288PubMedCentralCrossRefPubMed

20.

Xian X, Hakansson J, Stahlberg A, Lindblom P, Betsholtz C, Gerhardt H, Semb H: Pericytes limit tumor cell metastasis. J Clin Invest 2006, 116: 642–651. 10.1172/JCI25705PubMedCentralCrossRefPubMed

21.

Parangi S, O'Reilly M, Christofori G, Holmgren L, Grosfeld J, Folkman J, Hanahan D: Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proc Natl Acad Sci USA 1996, 93: 2002–2007. 10.1073/pnas.93.5.2002PubMedCentralCrossRefPubMed

22.

Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D: Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 1999, 284: 808–812. 10.1126/science.284.5415.808CrossRefPubMed

23.

Compagni A, Christofori G: Recent advances in research on multistage tumorigenesis. Br J Cancer 2000, 83: 1–5.PubMedCentralCrossRefPubMed

24.

Schomber T, Kopfstein L, Djonov V, Albrecht I, Baeriswyl V, Strittmatter K, Christofori G: Placental growth factor-1 attenuates vascular endothelial growth factor-a-dependent tumor angiogenesis during beta cell carcinogenesis. Cancer Res 2007, 67: 10840–10848. 10.1158/0008-5472.CAN-07-1034CrossRefPubMed

25.

Hanahan D: Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 1985, 315: 115–122. 10.1038/315115a0CrossRefPubMed

26.

Reubi JC, Laderach U, Waser B, Gebbers JO, Robberecht P, Laissue JA: Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. Cancer Res 2000, 60: 3105–3112.PubMed

27.

Reubi JC, Gugger M, Waser B, Schaer JC: Y₁-mediated effect of neuropeptide Y in cancer: breast carcinomas as targets. Cancer Res 2001, 61: 4636–4641.PubMed

28.

Ginj M, Hinni K, Tschumi S, Schulz S, Maecke HR: Trifunctional somatostatin-based derivatives designed for targeted radiotherapy using auger electron emitters. J Nucl Med 2005, 46: 2097–2103.PubMed

29.

Chicci GG, Cascieri MA, Graziano MP, Calahan T, Tota MR: Fluroescein-Trp25-exendin-4, a biologically active fluorescent probe for the human GLP-1 receptor. Peptides 1997, 8: 319–321.CrossRef

30.

Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, Christofori G: Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell 2006, 9: 261–272. 10.1016/j.ccr.2006.03.010CrossRefPubMed

31.

Klosowska-Wardega A, Hasumi Y, Burmakin M, Ahgren A, Stuhr L, Moen I, Reed RK, Rubin K, Hellberg C, Heldin CH: Combined anti-angiogenic therapy targeting PDGF and VEGF receptors lowers the interstitial fluid pressure in a murine experimental carcinoma. PLoS One 2009, 4: e8149. 10.1371/journal.pone.0008149PubMedCentralCrossRefPubMed

32.

Heskamp S, Boerman OC, Molkenboer-Kuenen JD, Oyen WJ, van der Graaf WT, van Laarhoven HW: Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti-insulin-like growth factor 1 receptor antibodies. Int J Cancer 2013, 133: 307–314. 10.1002/ijc.28046CrossRefPubMed

33.

Desar IM, Stillebroer AB, Oosterwijk E, Leenders WP, van Herpen CM, van der Graaf WT, Boerman OC, Mulders PF, Oyen WJ: ¹¹¹In-bevacizumab imaging of renal cell cancer and evaluation of neoadjuvant treatment with the vascular endothelial growth factor receptor inhibitor sorafenib. J Nucl Med 2010, 51: 1707–1715. 10.2967/jnumed.110.078030CrossRefPubMed

34.

Arjaans M, Oude Munnink TH, Oosting SF, van Scheltinga AG T, Gietema JA, Garbacik ET, Timmer-Bosscha H, Lub-de Hooge MN, Schröder CP, de Vries EG: Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake. Cancer Res 2013, 73: 3347–3355. 10.1158/0008-5472.CAN-12-3518CrossRefPubMed

35.

Van der Veldt AA, Lubberink M, Bahce I, Walraven M, de Boer MP, Greuter HN, Hendrikse NH, Eriksson J, Windhorst AD, Postmus PE, Verheul HM, Serné EH, Lammertsma AA, Smit EF: Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell 2012, 21: 82–91. 10.1016/j.ccr.2011.11.023CrossRefPubMed

36.

Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS: Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 1997, 151: 1523–1530.PubMedCentralPubMed

37.

Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P: Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011, 364: 501–513. 10.1056/NEJMoa1003825CrossRefPubMed

38.

Williams KJ, Telfer BA, Shannon AM, Babur M, Stratford IJ, Wedge SR: Inhibition of vascular endothelial growth factor signalling using cediranib (RECENTIN; AZD2171) enhances radiation response and causes substantial physiological changes in lung tumour xenografts. Br J Radiol 2008, 81(Spec 1):S21-S27.CrossRefPubMed

39.

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

40.

Schomber T, Zumsteg A, Strittmatter K, Crnic I, Antoniadis H, Littlewood-Evans A, Wood J, Christofori G: Differential effects of the vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 on tumor angiogenesis and tumor lymphangiogenesis. Mol Cancer Ther 2009, 8: 55–63.CrossRefPubMed

41.

Moll S, Nickeleit V, Mueller-Brand J, Brunner FP, Maecke HR, Mihatsch MJ: A new cause of renal thrombotic microangiopathy: yttrium 90-DOTATOC internal radiotherapy. Am J Kidney Dis 2001, 37: 847–851. 10.1016/S0272-6386(01)80135-9CrossRefPubMed

42.

Cornelissen B, Vallis KA: Targeting the nucleus: an overview of Auger-electron radionuclide therapy. Curr Drug Discov Technol 2010, 7: 263–279. 10.2174/157016310793360657CrossRefPubMed

43.

Goddu SM, Howell RW, Rao DV: Cellular dosimetry: absorbed fractions for monoenergetic electron and alpha particle sources and S-values for radionuclides uniformly distributed in different cell compartments. J Nucl Med 1994, 35: 303–316.PubMed

44.

Cai Z, Pignol JP, Chan C, Reilly RM: Cellular dosimetry of ¹¹¹In using Monte Carlo N-particle computer code: comparison with analytic methods and correlation with in vitro cytotoxicity. J Nucl Med 2010, 51: 462–470. 10.2967/jnumed.109.063156CrossRefPubMed

45.

Chen P, Wang J, Hope K, Jin L, Dick J, Cameron R, Brandwein J, Minden M, Reilly RM: Nuclear localizing sequences promote nuclear translocation and enhance the radiotoxicity of the anti-CD33 monoclonal antibody HuM195 labeled with 111In in human myeloid leukemia cells. J Nucl Med 2006, 47: 827–36.PubMed

Title: Synergism of peptide receptor-targeted Auger electron radiation therapy with anti-angiogenic compounds in a mouse model of neuroendocrine tumors
Authors: Andreas Wicki
Damian Wild
Vincent Prêtre
Rosalba Mansi
Annette Orleth
Jean-Claude Reubi
Christoph Rochlitz
Christoph Mamot
Helmut R Mäcke
Gerhard Christofori
Publication date: 01-12-2014
Publisher: Springer Berlin Heidelberg
Published in: EJNMMI Research / Issue 1/2014
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/2191-219X-4-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Synergism of peptide receptor-targeted Auger electron radiation therapy with anti-angiogenic compounds in a mouse model of neuroendocrine tumors

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2014

Heterogeneity of microsphere distribution in resected liver and tumour tissue following selective intrahepatic radiotherapy

The effect of volume of interest definition on quantification of lymph node immune response to a monkeypox virus infection assessed by 18F-FDG-PET

Multiparametric magnetic resonance in the assessment of the gender differences in a high-grade glioma rat model

Prediction of clinically relevant hyperkalemia in patients treated with peptide receptor radionuclide therapy

Camelid reporter gene imaging: a generic method for in vivo cell tracking

Bone Scan Index as a prognostic imaging biomarker during androgen deprivation therapy