Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma

Centre Antoine Lacassagne, Institute for Research on Cancer and Aging of Nice (IRCAN), University Nice Cote d’Azur, CNRS UMR 7284, INSERM U1081, 06189 Nice, France

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Department of Radiation Oncology, Centre Antoine-Lacassagne, University of Côte d’Azur, Fédération Claude Lalanne, 06189 Nice, France

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Team SOAP, CRCINA, INSERM, CNRS, Université de Nantes, 44000 Nantes, France

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Integrated Center of Oncology, 44800 St. Herblain, France

Authors to whom correspondence should be addressed.

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These authors contributed equally to this work.

Academic Editor: Michele Bernasconi

Cancers 2022, 14(1), 70; https://doi.org/10.3390/cancers14010070

Received: 8 November 2021 / Revised: 14 December 2021 / Accepted: 15 December 2021 / Published: 24 December 2021

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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Simple Summary

Medulloblastoma is the most frequent pediatric brain cancer. Despite great improvements in the treatment of this disease over the last decades, survivors are subject to debilitating adverse effects that strongly impair their quality of life. There is an urgent need to find efficient anticancer therapies with fewer toxic effects. In this study, we suggest that an FDA- and EMA-approved antiangiogenic compound named axitinib may display effective antitumoral effects and low toxicity towards children as compared to a reference treatment currently used in clinical protocols. We also show that this compound can enter the brain compartment and exert antitumoral effects in vivo. Our study paves the way towards a clinical trial of repurposing axitinib to a pediatric brain cancer indication.

Abstract

Background: Despite the improvement of medulloblastoma (MB) treatments, survivors face severe long-term adverse effects and associated morbidity following multimodal treatments. Moreover, relapses are fatal within a few months. Therefore, chemotherapies inducing fewer adverse effects and/or improving survival at relapse are key for MB patients. Our purpose was to evaluate the last-generation antiangiogenic drugs for their relevance in the therapeutic arsenal of MB. Methods: We screened three EMA- and FDA-approved antiangiogenic compounds (axitinib, cabozantinib and sunitinib) for their ability to reduce cell viability of five MB cell lines and their low toxicity towards two normal cell lines in vitro. Based on this screening, single-agent and combination therapies were designed for in vivo validation. Results: Axitinib, cabozantinib and sunitinib decreased viability of all the tested tumor cells. Although sunitinib was the most efficient in tumor cells, it also impacted normal cells. Therefore, axitinib showed the highest selectivity index for MB cells as compared to normal cells. The compound did not lead to acute toxicity in juvenile rats and crossed the blood–brain barrier. Moreover, axitinib efficiently reduced the growth rate of experimental brain tumors. Analysis of public databases showed that high expression of axitinib targets correlates with poor prognosis. Conclusion: Our results suggest that axitinib is a compelling candidate for MB treatment. View Full-Text

Keywords: pediatric brain cancer; medulloblastoma; targeted therapy; angiogenesis

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MDPI and ACS Style

Pagnuzzi-Boncompagni, M.; Picco, V.; Vial, V.; Planas-Bielsa, V.; Vandenberghe, A.; Daubon, T.; Derieppe, M.-A.; Montemagno, C.; Durivault, J.; Grépin, R.; Martial, S.; Doyen, J.; Gavard, J.; Pagès, G. Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma. Cancers 2022, 14, 70. https://doi.org/10.3390/cancers14010070

AMA Style

Pagnuzzi-Boncompagni M, Picco V, Vial V, Planas-Bielsa V, Vandenberghe A, Daubon T, Derieppe M-A, Montemagno C, Durivault J, Grépin R, Martial S, Doyen J, Gavard J, Pagès G. Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma. Cancers. 2022; 14(1):70. https://doi.org/10.3390/cancers14010070

Chicago/Turabian Style

Pagnuzzi-Boncompagni, Marina, Vincent Picco, Valérie Vial, Victor Planas-Bielsa, Ashaina Vandenberghe, Thomas Daubon, Marie-Alix Derieppe, Christopher Montemagno, Jérôme Durivault, Renaud Grépin, Sonia Martial, Jérôme Doyen, Julie Gavard, and Gilles Pagès. 2022. "Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma" Cancers 14, no. 1: 70. https://doi.org/10.3390/cancers14010070

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Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma

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