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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2017

Open Access 01-12-2017 | Research

The brain-penetrating CXCR4 antagonist, PRX177561, increases the antitumor effects of bevacizumab and sunitinib in preclinical models of human glioblastoma

Authors: Giovanni Luca Gravina, Andrea Mancini, Francesco Marampon, Alessandro Colapietro, Simona Delle Monache, Roberta Sferra, Flora Vitale, Peter J. Richardson, Lee Patient, Stephen Burbidge, Claudio Festuccia

Published in: Journal of Hematology & Oncology | Issue 1/2017

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Abstract

Background

Glioblastoma recurrence after treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. It has been demonstrated that anti-VEGF/VEGFR therapies control the invasive phenotype and that relapse occurs through the increased activity of CXCR4. We therefore hypothesized that combining bevacizumab or sunitinib with the novel CXCR4 antagonist, PRX177561, would have superior antitumor activity.

Methods

The effects of bevacizumab, sunitinib, and PRX177561 were tested alone or in combination in subcutaneous xenografts of U87MG, U251, and T98G cells as well as on intracranial xenografts of luciferase tagged U87MG cells injected in CD1-nu/nu mice. Animals were randomized to receive vehicle, bevacizumab (4 mg/kg iv every 4 days), sunitinib (40 mg/kg po qd), or PRX177561 (50 mg/kg po qd).

Results

The in vivo experiments demonstrated that bevacizumab and sunitinib increase the in vivo expression of CXCR4, SDF-1α, and TGFβ1. In addition, we demonstrate that the co-administration of the novel brain-penetrating CXCR4 antagonist, PRX177561, with bevacizumab or sunitinib inhibited tumor growth and reduced the inflammation. The combination of PRX177561 with bevacizumab resulted in a synergistic reduction of tumor growth with an increase of disease-free survival (DSF) and overall survival (OS), whereas the combination of PRX177561 with sunitinib showed a mild additive effect.

Conclusions

The CXC4 antagonist PRX177561 may be a valid therapeutic complement to anti-angiogenic therapy, particularly when used in combination with VEGF/VEGFR inhibitors. Therefore, this compound deserves to be considered for future clinical evaluation.
Literature
1.
Han SJ, Englot DJ, Birk H, Molinaro AM, Chang SM, Clarke JL, Prados MD, Taylor JW, Berger MS, Butowski NA. Impact of timing of concurrent chemoradiation for newly diagnosed glioblastoma: a critical review of current evidence. Neurosurgery. 2015;62:160–5.CrossRefPubMed
2.
Kim SS, Harford JB, Pirollo KF, Chang EH. Effective treatment of glioblastoma requires crossing the blood-brain barrier and targeting tumors including cancer stem cells: the promise of nanomedicine. Biochem Biophys Res Commun. 2015;468:485–9.CrossRefPubMedPubMedCentral
3.
Zhang M, Ye G, Li J, Wang Y. Recent advance in molecular angiogenesis in glioblastoma: the challenge and hope for anti-angiogenic therapy. Brain Tumor Pathol. 2015;32:229–36.CrossRefPubMed
4.
Tamura R, Tanaka T, Miyake K, Tabei Y, Ohara K, Sampetrean O, Kono M, Mizutani K, Yamamoto Y, Murayama Y, Tamiya T, Yoshida K, Sasaki H. Histopathological investigation of glioblastomas resected under bevacizumab treatment. Oncotarget. 2016. doi: 10.​18632/​oncotarget.​9387.
5.
Mathieu V, De Nève N, Le Mercier M, Dewelle J, Gaussin JF, Dehoux M, Kiss R, Lefranc F. Combining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in a human glioblastoma orthotopic xenograft model. Neoplasia. 2008;10(12):1383–92.CrossRefPubMedPubMedCentral
6.
Cortes-Santiago N, Hossain MB, Gabrusiewicz K, Fan X, Gumin J, Marini FC, Alonso MM, Lang F, Yung WK, Fueyo J, Gomez-Manzano C. Soluble Tie2 overrides the heightened invasion induced by anti-angiogenesis therapies in gliomas. Oncotarget. 2016;7:16146–57.PubMedPubMedCentral
7.
D’Amico R, Lei L, Kennedy BC, Sisti J, Ebiana V, Crisman C, Christensen JG, Gil O, Rosenfeld SS, Canoll P, Bruce JN. The addition of sunitinib to radiation delays tumor growth in a murine model of glioblastoma. Neurol Res. 2012;34(3):252–61.CrossRefPubMed
8.
Lucio-Eterovic AK, Piao Y, de Groot JF. Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy. Clin Cancer Res. 2009;15(14):4589–99.CrossRefPubMed
9.
DeLay M, Jahangiri A, Carbonell WS, Hu YL, Tsao S, Tom MW, Paquette J, Tokuyasu TA, Aghi MK. Microarray analysis verifies two distinct phenotypes of glioblastomas resistant to antiangiogenic therapy. Clin Cancer Res. 2012;18(10):2930–42.CrossRefPubMedPubMedCentral
10.
Okamoto S, Nitta M, Maruyama T, Sawada T, Komori T, Okada Y, Muragaki Y. Bevacizumab changes vascular structure and modulates the expression of angiogenic factors in recurrent malignant gliomas. Brain Tumor Pathol. 2016;33(2):129–36.CrossRefPubMed
11.
Kessler T, Sahm F, Blaes J, Osswald M, Rübmann P, Milford D, Urban S, Jestaedt L, Heiland S, Bendszus M, Hertenstein A, Pfenning PN, Ruiz de Almodóvar C, Wick A, Winkler F, von Deimling A, Platten M, Wick W, Weiler M. Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma. Oncotarget. 2015;6(31):31050–68.PubMedPubMedCentral
12.
Kang W, Kim SH, Cho HJ, Jin J, Lee J, Joo KM, Nam DH. Talin1 targeting potentiates anti-angiogenic therapy by attenuating invasion and stem-like features of glioblastoma multiforme. Oncotarget. 2015;6(29):27239–51.CrossRefPubMedPubMedCentral
13.
Hu YL, DeLay M, Jahangiri A, Molinaro AM, Rose SD, Carbonell WS, Aghi MK. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res. 2012;72(7):1773–83.CrossRefPubMedPubMedCentral
14.
Xu H, Rahimpour S, Nesvick CL, Zhang X, Ma J, Zhang M, Zhang G, Wang L, Yang C, Hong CS, Germanwala AV, Elder JB, Ray-Chaudhury A, Yao Y, Gilbert MR, Lonser RR, Heiss JD, Brady RO, Mao Y, Qin J, Zhuang Z. Activation of hypoxia signaling induces phenotypic transformation of glioma cells: implications for bevacizumab antiangiogenic therapy. Oncotarget. 2015;6:11882–93.CrossRefPubMedPubMedCentral
15.
Piao Y, Park SY, Henry V, Smith BD, Tiao N, Flynn DL, de Groot JF. Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models. Neuro Oncol. 2016;18:1230-41.
16.
Scholz A, Harter PN, Cremer S, Yalcin BH, Gurnik S, Yamaji M, Di Tacchio M, Sommer K, Baumgarten P, Bähr O, Steinbach JP, Trojan J, Glas M, Herrlinger U, Krex D, Meinhardt M, Weyerbrock A, Timmer M, Goldbrunner R, Deckert M, Braun C, Schittenhelm J, Frueh JT, Ullrich E, Mittelbronn M, Plate KH, Reiss Y. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma. EMBO Mol Med. 2015;8:39–57.CrossRefPubMedPubMedCentral
17.
Gabrusiewicz K, Liu D, Cortes-Santiago N, Hossain MB, Conrad CA, Aldape KD, Fuller GN, Marini FC, Alonso MM, Idoate MA, Gilbert MR, Fueyo J, Gomez-Manzano C. Anti-vascular endothelial growth factor therapy-induced glioma invasion is associated with accumulation of Tie2-expressing monocytes. Oncotarget. 2014;5:2208–20.CrossRefPubMedPubMedCentral
18.
Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D, Isachenko N, Fouse SD, Phillips JJ, Cheresh DA, Park M, Bergers G. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell. 2012;22(1):21–35.CrossRefPubMedPubMedCentral
19.
Kuczynski EA, Patten SG, Coomber BL. VEGFR2 expression and TGF-β signaling in initial and recurrent high-grade human glioma. Oncology. 2011;81(2):126–34.CrossRefPubMed
20.
Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK. CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin Cancer Res. 2011;17(8):2074–80.CrossRefPubMedPubMedCentral
21.
Barone A, Sengupta R, Warrington NM, Smith E, Wen PY, Brekken RA, Romagnoli B, Douglas G, Chevalier E, Bauer MP, Dembowsky K, Piwnica-Worms D, Rubin JB. Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and synergistically improves survival in an intracranial mouse model of glioblastoma. Oncotarget. 2014;5:9811–22.CrossRefPubMedPubMedCentral
22.
Pham K, Luo D, Siemann DW, Law BK, Reynolds BA, Hothi P, Foltz G, Harrison JK. VEGFR inhibitors upregulate CXCR4 in VEGF receptor-expressing glioblastoma in a TGFβR signaling-dependent manner. Cancer Lett. 2015;360:60–7.CrossRefPubMed
23.
Liu Y, Carson-Walter E, Walter KA. Targeting chemokine receptor CXCR7 inhibits glioma cell proliferation and mobility. Anticancer Res. 2015;35:53–64.PubMed
24.
Würth R, Bajetto A, Harrison JK, Barbieri F, Florio T. CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment. Front Cell Neurosci. 2014;8:144.PubMedPubMedCentral
25.
Festuccia C, Gravina GL, D’Alessandro AM, Muzi P, Millimaggi D, Dolo V, Ricevuto E, Vicentini C, Bologna M. Azacitidine improves antitumor effects of docetaxel and cisplatin in aggressive prostate cancer models. Endocr Relat Cancer. 2009;16:401–13.CrossRefPubMed
26.
Gravina GL, Marampon F, Sherris D, Vittorini F, Di Cesare E, Tombolini V, Lenzi A, Jannini EA, Festuccia C. Torc1/Torc2 inhibitor, Palomid 529, enhances radiation response modulating CRM1-mediated survivin function and delaying DNA repair in prostate cancer models. Prostate. 2014;74:852–68.CrossRefPubMed
27.
28.
Reynolds CP, Sun B, DeClerck BA, Moats RA. Assessing growth and response to therapy in murine tumor models. In: Rosalyn B, editor. Methods in molecular medicine: chemosensitivity, In vivo models, imaging, and molecular regulator. IIth ed. 2005. p. 335–441.
29.
Arpino G, Gutierrez C, Weiss H, Rimawi M, Massarweh S, Bharwan L, De Placido S, Osborne CK, Schiff R. Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst. 2007;99:694–705.CrossRefPubMed
30.
Bruzzese F, Di Gennaro E, Avallone A, Pepe S, Arra C, Caraglia M, Tagliaferri P, Budillon A. Synergistic antitumor activity of epidermal growth factor receptor tyrosine kinase inhibitor gefitinib and IFN-alpha in head and neck cancer cells in vitro and in vivo. Clin Cancer Res. 2006;12:617–25.CrossRefPubMed
31.
Ricard C, Stanchi F, Rougon G, Debarbieux F. An orthotopic glioblastoma mouse model maintaining brain parenchymal physical constraints and suitable for intravital two-photon microscopy. J Vis Exp. 2014;(86). doi:10.​3791/​51108.
32.
Altman D. Practical statistics for medical research. London: Chapman & Hall; 1991.
33.
Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008;70:779–87.CrossRefPubMed
34.
Baker GJ, Yadav VN, Motsch S, Koschmann C, Calinescu AA, Mineharu Y, Camelo-Piragua SI, Orringer D, Bannykh S, Nichols WS, deCarvalho AC, Mikkelsen T, Castro MG, Lowenstein PR. Mechanisms of glioma formation: iterative perivascular glioma growth and invasion leads to tumor progression, VEGF-independent vascularization, and resistance to antiangiogenic therapy. Neoplasia. 2014;16:543–61.CrossRefPubMedPubMedCentral
35.
Xu L, Duda DG, di Tomaso E, Ancukiewicz M, Chung DC, Lauwers GY, Samuel R, Shellito P, Czito BG, Lin PC, Poleski M, Bentley R, Clark JW, Willett CG, Jain RK. Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res. 2009;69:7905–10.CrossRefPubMedPubMedCentral
36.
Kuroda J, Kuratsu J, Yasunaga M, Koga Y, Kenmotsu H, Sugino T, Matsumura Y. Antitumor effect of NK012, a 7-ethyl-10-hydroxycamptothecin-incorporating polymeric micelle, on U87MG orthotopic glioblastoma in mice compared with irinotecan hydrochloride in combination with bevacizumab. Clin Cancer Res. 2010;16:521–9.CrossRefPubMed
37.
de Boüard S, Herlin P, Christensen JG, Lemoisson E, Gauduchon P, Raymond E, Guillamo JS. Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma. Neuro Oncol. 2007;9:412–23.CrossRefPubMedPubMedCentral
38.
Ali MM, Kumar S, Shankar A, Varma NR, Iskander AS, Janic B, Chwang WB, Jain R, Babajeni-Feremi A, Borin TF, Bagher-Ebadian H, Brown SL, Ewing JR, Arbab AS. Effects of tyrosine kinase inhibitors and CXCR4 antagonist on tumor growth and angiogenesis in rat glioma model: MRI and protein analysis study. Transl Oncol. 2013;6:660–939.CrossRefPubMedPubMedCentral
39.
Gravina GL, Mancini A, Sanita P, Vitale F, Marampon F, Ventura L, Landesman Y, McCauley D, Kauffman M, Shacham S, Festuccia C. KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and surviving in prostate cancer models. BMC Cancer. 2015;15:94140.CrossRef
40.
Gravina GL, Mancini A, Colapietro A,.Vitale F., Vetuschi A. Pompili S., Rossi G. Marampon F., Richardson PJ, Patient L, Burbdgle S and Festuccia C. The novel CXCR4 antagonist, PRX177561, reduces tumor cell proliferation and accelerates cancer stem cell differentiation in Glioblastoma preclinical models Tumor Biology, 2017 in press
41.
Tabouret E, Tchoghandjian A, Denicolai E, Delfino C, Metellus P, Graillon T, Boucard C, Nanni I, Padovani L, Ouafik L, Figarella-Branger D, Chinot O. Recurrence of glioblastoma after radio-chemotherapy is associated with an angiogenic switch to the CXCL12-CXCR4 pathway. Oncotarget. 2015;6:11664–75.CrossRefPubMedPubMedCentral
42.
Flüh C, Hattermann K, Mehdorn HM, Synowitz M, Held-Feindt J. Differential expression of CXCR4 and CXCR7 with various stem cell markers in paired human primary and recurrent glioblastomas. Int J Oncol. 2016;48:1408-16.
43.
Festuccia C, Bologna M, Gravina GL, Guerra F, Angelucci A, Villanova I, Millimaggi D, Teti A. Osteoblast conditioned media contain TGF-beta1 and modulate the migration of prostate tumor cells and their interactions with extracellular matrix components. Int J Cancer. 1999;81:395–403.CrossRefPubMed
44.
Ataka K, Asakawa A, Nagaishi K, Kaimoto K, Sawada A, Hayakawa Y, Tatezawa R, Inui A, Fujimiya M. Bone marrow-derived microglia infiltrate into the paraventricular nucleus of chronic psychological stress-loaded mice. PLoS One. 2013;8:e81744.CrossRefPubMedPubMedCentral
45.
Stec M, Baran J, Baj-Krzyworzeka M, Weglarczyk K, Gozdzik J, Siedlar M, Zembala M. Chemokine receptors and chemokine production by CD34+ stem cell-derived monocytes in response to cancer cells. Anticancer Res. 2012;32:4749–53.PubMed
46.
Gatti M, Pattarozzi A, Bajetto A, Würth R, Daga A, Fiaschi P, Zona G, Florio T, Barbieri F. Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity. Toxicology. 2013;314:209–20.CrossRefPubMed
47.
Pettersson S, Pérez-Nueno VI, Ros-Blanco L, Puig de La Bellacasa R, Rabal MO, Batllori X, Clotet B, Clotet-Codina I, Armand-Ugón M, Esté J, Borrell JI, Teixidó J. Discovery of novel non-cyclam polynitrogenated CXCR4 coreceptor inhibitors. ChemMedChem. 2008;3:1549–57.CrossRefPubMed
48.
Lulli V, Buccarelli M, Martini M, Signore M, Biffoni M, Giannetti S, Morgante L, Marziali G, Ilari R, Pagliuca A, Larocca LM, De Maria R, Pallini R, Ricci-Vitiani L. miR-135b suppresses tumorigenesis in glioblastoma stem-like cells impairing proliferation, migration and self-renewal. Oncotarget. 2015;6:37241–56. doi:10.​18632/​oncotarget.​5925.PubMedPubMedCentral
49.
Abdelouahab H, Zhang Y, Wittner M, Oishi S, Fujii N, Besancenot R, Plo I, Ribrag V, Solary E, Vainchenker W, Barosi G, Louache F. CXCL12/CXCR4 pathway is activated by oncogenic JAK2 in a PI3K-dependent manner. Oncotarget. 2016. doi: 10.​18632/​oncotarget.​10789.
Metadata
Title
The brain-penetrating CXCR4 antagonist, PRX177561, increases the antitumor effects of bevacizumab and sunitinib in preclinical models of human glioblastoma
Authors
Giovanni Luca Gravina
Andrea Mancini
Francesco Marampon
Alessandro Colapietro
Simona Delle Monache
Roberta Sferra
Flora Vitale
Peter J. Richardson
Lee Patient
Stephen Burbidge
Claudio Festuccia
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2017
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-016-0377-8

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