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1. Exploiting Integrin-αVβ3 to Enhance Radiotherapy Efficacy in Medulloblastoma via Ferroptosis.

Author

Gotorbe, Célia, Segui, Fabien, Echavidre, William, Durivault, Jérôme, Blanchard, Thays, Vial, Valérie, Pagnuzzi-Boncompagni, Marina, Villeneuve, Rémy, Amblard, Régis, Garnier, Nicolas, Ortholan, Cécile, Serrano, Benjamin, Picco, Vincent, Pouysségur, Jacques, Vucetic, Milica, and Montemagno, Christopher

Subjects
GLUTATHIONE peroxidase, MEDULLOBLASTOMA, BRAIN tumors, CELL death, OXIDATIVE stress
Abstract

Medulloblastoma, a malignant pediatric brain tumor, has a poor prognosis upon relapse, highlighting a critical clinical need. Our previous research linked medulloblastoma cell radioresistance to integrin-αvβ3 expression. β3-depleted (β3_KO) medulloblastoma cells exhibit lipid hydroxyperoxide accumulation after radiotherapy, indicating ferroptosis, a regulated cell death induced by ROS and inhibited by antioxidants such as cysteine, glutathione (GSH), and glutathione peroxidase 4 (GPx4). However, the link between αvβ3 expression, ferroptosis inhibition, and sensitivity to radiotherapy remains unclear. We showed that irradiated β3_KO medulloblastoma cells primarily die by ferroptosis, with β3-subunit expression correlating with radiotherapy sensitivity and anti-ferroptotic protein levels. Our findings suggest that integrin-αvβ3 signaling boosts oxidative stress resilience via mTORC1. Thus, targeting integrin-αvβ3 could enhance radiotherapy efficacy in medulloblastoma by inducing ferroptotic cell death. [ABSTRACT FROM AUTHOR]

Published
2024
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3. FIGURE 4 from Integrin-αvβ3 is a Therapeutically Targetable Fundamental Factor in Medulloblastoma Tumorigenicity and Radioresistance

Author

Echavidre, William, primary, Durivault, Jérôme, primary, Gotorbe, Célia, primary, Blanchard, Thays, primary, Pagnuzzi, Marina, primary, Vial, Valérie, primary, Raes, Florian, primary, Broisat, Alexis, primary, Villeneuve, Rémy, primary, Amblard, Régis, primary, Garnier, Nicolas, primary, Ortholan, Cécile, primary, Faraggi, Marc, primary, Serrano, Benjamin, primary, Picco, Vincent, primary, and Montemagno, Christopher, primary

Published
2023
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4. Figure S1 from Integrin-αvβ3 is a Therapeutically Targetable Fundamental Factor in Medulloblastoma Tumorigenicity and Radioresistance

Author

Echavidre, William, primary, Durivault, Jérôme, primary, Gotorbe, Célia, primary, Blanchard, Thays, primary, Pagnuzzi, Marina, primary, Vial, Valérie, primary, Raes, Florian, primary, Broisat, Alexis, primary, Villeneuve, Rémy, primary, Amblard, Régis, primary, Garnier, Nicolas, primary, Ortholan, Cécile, primary, Faraggi, Marc, primary, Serrano, Benjamin, primary, Picco, Vincent, primary, and Montemagno, Christopher, primary

Published
2023
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5. FIGURE 2 from Integrin-αvβ3 is a Therapeutically Targetable Fundamental Factor in Medulloblastoma Tumorigenicity and Radioresistance

Author

Echavidre, William, primary, Durivault, Jérôme, primary, Gotorbe, Célia, primary, Blanchard, Thays, primary, Pagnuzzi, Marina, primary, Vial, Valérie, primary, Raes, Florian, primary, Broisat, Alexis, primary, Villeneuve, Rémy, primary, Amblard, Régis, primary, Garnier, Nicolas, primary, Ortholan, Cécile, primary, Faraggi, Marc, primary, Serrano, Benjamin, primary, Picco, Vincent, primary, and Montemagno, Christopher, primary

Published
2023
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6. FIGURE 6 from Integrin-αvβ3 is a Therapeutically Targetable Fundamental Factor in Medulloblastoma Tumorigenicity and Radioresistance

Author

Echavidre, William, primary, Durivault, Jérôme, primary, Gotorbe, Célia, primary, Blanchard, Thays, primary, Pagnuzzi, Marina, primary, Vial, Valérie, primary, Raes, Florian, primary, Broisat, Alexis, primary, Villeneuve, Rémy, primary, Amblard, Régis, primary, Garnier, Nicolas, primary, Ortholan, Cécile, primary, Faraggi, Marc, primary, Serrano, Benjamin, primary, Picco, Vincent, primary, and Montemagno, Christopher, primary

Published
2023
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7. FIGURE 3 from Integrin-αvβ3 is a Therapeutically Targetable Fundamental Factor in Medulloblastoma Tumorigenicity and Radioresistance

Author

Echavidre, William, primary, Durivault, Jérôme, primary, Gotorbe, Célia, primary, Blanchard, Thays, primary, Pagnuzzi, Marina, primary, Vial, Valérie, primary, Raes, Florian, primary, Broisat, Alexis, primary, Villeneuve, Rémy, primary, Amblard, Régis, primary, Garnier, Nicolas, primary, Ortholan, Cécile, primary, Faraggi, Marc, primary, Serrano, Benjamin, primary, Picco, Vincent, primary, and Montemagno, Christopher, primary

Published
2023
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8. FIGURE 5 from Integrin-αvβ3 is a Therapeutically Targetable Fundamental Factor in Medulloblastoma Tumorigenicity and Radioresistance

Author

Echavidre, William, primary, Durivault, Jérôme, primary, Gotorbe, Célia, primary, Blanchard, Thays, primary, Pagnuzzi, Marina, primary, Vial, Valérie, primary, Raes, Florian, primary, Broisat, Alexis, primary, Villeneuve, Rémy, primary, Amblard, Régis, primary, Garnier, Nicolas, primary, Ortholan, Cécile, primary, Faraggi, Marc, primary, Serrano, Benjamin, primary, Picco, Vincent, primary, and Montemagno, Christopher, primary

Published
2023
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9. Table S1 from Integrin-αvβ3 is a Therapeutically Targetable Fundamental Factor in Medulloblastoma Tumorigenicity and Radioresistance

Author

Echavidre, William, primary, Durivault, Jérôme, primary, Gotorbe, Célia, primary, Blanchard, Thays, primary, Pagnuzzi, Marina, primary, Vial, Valérie, primary, Raes, Florian, primary, Broisat, Alexis, primary, Villeneuve, Rémy, primary, Amblard, Régis, primary, Garnier, Nicolas, primary, Ortholan, Cécile, primary, Faraggi, Marc, primary, Serrano, Benjamin, primary, Picco, Vincent, primary, and Montemagno, Christopher, primary

Published
2023
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10. Data from Integrin-αvβ3 is a Therapeutically Targetable Fundamental Factor in Medulloblastoma Tumorigenicity and Radioresistance

Author

Echavidre, William, primary, Durivault, Jérôme, primary, Gotorbe, Célia, primary, Blanchard, Thays, primary, Pagnuzzi, Marina, primary, Vial, Valérie, primary, Raes, Florian, primary, Broisat, Alexis, primary, Villeneuve, Rémy, primary, Amblard, Régis, primary, Garnier, Nicolas, primary, Ortholan, Cécile, primary, Faraggi, Marc, primary, Serrano, Benjamin, primary, Picco, Vincent, primary, and Montemagno, Christopher, primary

Published
2023
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11. FIGURE 1 from Integrin-αvβ3 is a Therapeutically Targetable Fundamental Factor in Medulloblastoma Tumorigenicity and Radioresistance

Author

Echavidre, William, primary, Durivault, Jérôme, primary, Gotorbe, Célia, primary, Blanchard, Thays, primary, Pagnuzzi, Marina, primary, Vial, Valérie, primary, Raes, Florian, primary, Broisat, Alexis, primary, Villeneuve, Rémy, primary, Amblard, Régis, primary, Garnier, Nicolas, primary, Ortholan, Cécile, primary, Faraggi, Marc, primary, Serrano, Benjamin, primary, Picco, Vincent, primary, and Montemagno, Christopher, primary

Published
2023
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12. Integrin-αvβ3 is a therapeutically targetable fundamental factor in medulloblastoma tumorigenicity and radioresistance

Author

Echavidre, William, primary, Durivault, Jerome, additional, Gotorbe, Célia, additional, Blanchard, Thays, additional, Pagnuzzi, Marina, additional, Vial, Valérie, additional, Raes, Florian, additional, Broisat, Alexis, additional, Villeneuve, Rémy, additional, Amblard, Régis, additional, Garnier, Nicolas, additional, Ortholan, Cécile, additional, Faraggi, Marc, additional, Serrano, Benjamin, additional, Picco, Vincent, additional, and Montemagno, Christopher, additional

Published
2023
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16. Integrin-alpha V beta 3 is a fundamental factor in medulloblastoma tumorigenicity and radioresistance: A new game for an old player

Author

Echavidre, William, primary, Durivault, Jerome, additional, Gotorbe, Celia, additional, Blanchard, Thays, additional, Pagnuzzi, Marina, additional, Vial, Valerie, additional, Raes, Florian, additional, Broisat, Alexis, additional, Villeneuve, Remy, additional, Amblard, Regis, additional, Garnier, Nicolas, additional, Ortholan, Cecile, additional, Faraggi, Marc, additional, Serrano, Benjamin, additional, Picco, Vincent, additional, and Montemagno, Christopher, additional

Published
2023
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17. Targeting of the ELR+CXCL/CXCR1/2 Pathway Is a Relevant Strategy for the Treatment of Paediatric Medulloblastomas

Author

Penco-Campillo, Manon, primary, Molina, Clément, additional, Piris, Patricia, additional, Soufi, Nouha, additional, Carré, Manon, additional, Pagnuzzi-Boncompagni, Marina, additional, Picco, Vincent, additional, Dufies, Maeva, additional, Ronco, Cyril, additional, Benhida, Rachid, additional, Martial, Sonia, additional, and Pagès, Gilles, additional

Published
2022
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20. Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma

Author

Pagnuzzi-Boncompagni, Marina, primary, Picco, Vincent, additional, Vial, Valérie, additional, Planas-Bielsa, Victor, additional, Vandenberghe, Ashaina, additional, Daubon, Thomas, additional, Derieppe, Marie-Alix, additional, Montemagno, Christopher, additional, Durivault, Jérôme, additional, Grépin, Renaud, additional, Martial, Sonia, additional, Doyen, Jérôme, additional, Gavard, Julie, additional, and Pagès, Gilles, additional

Published
2021
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21. The antiangiogenic compound axitinib demonstrates low toxicity and anti-tumoral effects against medulloblastoma

Author

Pagnuzzi-Boncompagni, Marina, primary, Picco, Vincent, additional, Vial, Valerie, additional, Planas-Bielsa, Victor, additional, Vandenberghe, Ashaina, additional, Grepin, Renaud, additional, Durivault, Jerome, additional, Montemagno, Christopher, additional, Martial, Sonia, additional, Doyen, Jerome, additional, Gavard, Julie, additional, and Pages, Gilles, additional

Published
2020
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22. Unexpected Effects of Photontherapy and Protontherapy on VEGFC Production and Tumor Aggressiveness in Different Medulloblastoma Subgroups

Author

Comoglio, Yannick, Javier, Alvaro, Morel, Feliz, Hanna, Rita, Leloire, Magalie, Pagnuzzi, Marina, Durivault, Jerome, Picco, Vincent, Claren, Audrey, Doyen, Jérôme, Pagès Ab, Gilles, Martial, Sonia, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]
Abstract

International audience; Medulloblastoma (MB) is the most common malignant cerebellar pediatric tumor. MB is a heterogeneous pathology composed of four molecular subgroups, with variable prognoses depending on the subgroup. MB treatment includes surgical resection of the tumor, craniospinal X-ray irradiation (the reference treatment of most cancers) and adjuvant chemotherapy. Despite this treatment, 30% of the patients relapse. Their progression is marked by the fatal appearance of metastases within 5 years. According to the current dogma, the major actors of metastatic dissemination are the lymphatic vessel growth factor, VEGFC, and its receptor, VEGFR3, in most cancers. Protontherapy, which allows higher precision of tumor targeting while reducing side effects and radio-induced cancers, is now emerging as an alternative treatment of MB. In this work, we meant to demonstrate the differential biological effects of protontherapy and photontherapy on MB, as a model of both brain and pediatric tumors. We repeatedly irradiated MB cell lines by high doses (8 Gy) of X-rays, low-energy protons or high-energy protons (Proteus® One equipment, IBA, Belgium), thus generating resistant cells for each form of irradiation. We measured the production of VEGFA (angiogenesis), VEGFC (as a read-out of lymphangiogenesis programming), and ELR+CXCL cytokines (inflammation). We also determined the aggressiveness of the cells by proliferation, migration, and pseudo-vessel formation assays. Finally, we measured the epithelial-to-mesenchymal transition status of the cells and the apparent stemness of the cells after irradiation. We demonstrated that X-ray resistant cells presented an increase in VEGFC production, thus pleading for a cell programming in favor of the generation of new lymphatic vessels. Unexpectedly, however, these cells showed lower aggressiveness than their naïve counterparts. Moreover, we demonstrated that, opposite to the admitted higher effect of protontherapy over photontherapy (EBR = 1.1), proton beams were less harmful to MB cells than photon beams, when these cells were irradiated in the same conditions as patients. Hence, our results present striking new evidence that i) VEGFC is a negative regulator of irradiation-induced MB aggressiveness; ii) opposite to the common dogma, proton irradiation reduces irradiation-induced damage to MB cells.

Published
2019

23. UNCONVENTIONAL ROLE OF VEGFC AND LYMPHATIC VESSELS ON MEDULLOBLASTOMA CELL FATE

Author

Durivault, Jerome, Comoglio, Yannick, Hanna, Rita, Picco, Vincent, Javier, Alvaro, Morel, Feliz, Leloire, Magalie, Morot, Amandine, Pagnuzzi, Marina, Durivault, Jérôme, Pagès Ab, Gilles, Martial, Sonia, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]
Abstract

International audience; Medulloblastoma (MB) is the most common malignant cerebellar pediatric tumor. MB is a heterogeneous pathology composed of four molecular subgroups, with variable prognoses depending on the subgroup. MB treatment includes surgical resection of the tumor, craniospinal X-ray irradiation and adjuvant chemotherapy. Despite this treatment, 30% of the patients relapse. Their progression is marked by the fatal appearance of metastases within 5 years. The major actors of metastatic dissemination are the lymphatic vessel growth factor, VEGFC, and its receptor, VEGFR3. According to the current dogma, the lymphatic network is one of the main ways of tumor cell spreading. In this work, we meant to i) correlate VEGFC expression and MB aggressiveness; ii) determine the relevance of developing therapeutic strategies targeting the VEGFC / VEGFR3 axis. We showed that VEGFC mRNA expression is inversely correlated to cell aggressiveness. VEGFC decreased proliferation and migration of MB cell lines and promoted in vitro pseudo-vessel formation by MB cells. We generated irradiation-resistant cells and demonstrated that aggressive irradiation resistant-cells presented enhanced levels of VEGFC. Moreover, they acquired the ability to form vessel-like structures. Cells ectopically overexpressing VEGFC and irradiation-resistant cells formed smaller experimental tumors in nude mice. Opposite to the common dogma, our results give strong arguments to the role of VEGFC as a negative regulator of MB growth. However, VEGFC effect as for tumor dissemination might be MB subgroup dependent. Therefore, the use of VEGFC/VEGFR3 axis inhibitors to fight these tumors has to be considered with caution.

Published
2018

24. Additional file 11: of AKT1 restricts the invasive capacity of head and neck carcinoma cells harboring a constitutively active PI3 kinase activity

Author

Brolih, Sanja, Parks, Scott, Vial, Valérie, Durivault, Jérôme, Mostosi, Livio, Pouysségur, Jacques, Pagès, Gilles, and Picco, Vincent

Subjects
macromolecular substances
Abstract

Figure S2 Analysis of e-cadherin expression and localization by immunofluorescence in CAL33 cells. Immunostaining of e-cadherin (green) and Alexa555-phalloidin (red) staining of the actin cytoskeleton (F-actin) in CAL33 cells expressing a control shRNA (shCont), an shRNA sequences targeting AKT1 (sh1.2) or control cells treated with the pan-AKT inhibitor MK-2206 (MK), Rapamycin (Rapa) or Erlotinib (Erlo). Nuclear DNA was counterstained with Hoechst 33,342 (blue). (PDF 1545 kb)

Published
2018
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25. INTRINSIC OR INDUCED AGGRESSIVENESS-LINKED REGULATION OF VEGFC IN MEDULLOBLASTOMA CELL LINES

Author

Durivault, Jerome, Comoglio, Yannick, Hanna, Rita, Picco, Vincent, Javier, Alvaro, Morel, Feliz, Leloire, Magalie, Morot, Amandine, Pagnuzzi, Marina, Durivault, Jérôme, Pagès Ab, Gilles, Martial, Sonia, MARTIAL, Sonia, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]
Abstract

International audience; Medulloblastoma (MDB) is the most common pediatric malignant brain tumor. MDB is a very heterogeneous disease that consists of four subgroups, each of them with different molecular profiles, metastasis status and clinical outcomes. Treatment of MDB includes surgery, radiotherapy and chemotherapy. It cures 70% of the pa'ents nevertheless with many side effects. Relapse is always fatal. Understanding the mechanisms of this relapse might lead to the development of new targeted treatments. VEGFC and lympha'c markers are the main actors of the metasta'c process in many tumors. We thus meant to determine their role and regula'on in MDB-derived cells. We demonstrated that low-aggressiveness MDB-derived cells, DAOY, expressed high basal amounts of lympha'c marker mRNAs and proteins (VEGFC, PROX1, NRP2). Conversely, highly aggressive cells, HD-MB03, presented low amounts of these markers. X-ray irradia'on treatment of the cells induced a rise in VEGFC, at the mRNA and protein levels. We thus ques'oned the regula'on of lympha'c markers in MDB cells. We observed that in the highly aggressive HD-MB03 cells, VEGFC mRNA amount relies upon a very ac've NF-κB-dependent promoter, but that the mRNA gets intensely degraded, hence the low level of VEGFC mRNA in these cells. Conversely, DAOY cells present low ac'vity of VEGFC promoter and high stability of the synthesized mRNA. The promoter ac'vity is independent from NF-κB. Moreover, while VEGFC is secreted in DAOY cells, it is retained inside the cytoplasm of HD-MB03 cells. Since VEGFC is so precisely regulated in MDB cells, it may play an important part in MDB aggressiveness. HSP 90 VEGFC Claudin DAOY Clone 1 HD-MB03 DAPI DAPI DAPI VEGFC VEGFC VEGFC Merge Merge Merge Intrinsic characterisOcs of MB cell lines DAOY (SHH): High expression of lymphaOc markers and VEGFC > Low proliferaOon and high migraOon rates HDMB-03 (Grp3): High expression of lymphaOc markers and VEGFC > High proliferaOon and low migraOon rates VEGFC has a impact on the proliferaOon of HD-MB03 cells. VEGFC DAOY VEGFC promoter VEGFC VEGFC mRNA HD-MB03

Published
2018

33. TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells

Author

Biroccio, Annamaria, primary, Cherfils-Vicini, Julien, additional, Augereau, Adeline, additional, Pinte, Sébastien, additional, Bauwens, Serge, additional, Ye, Jing, additional, Simonet, Thomas, additional, Horard, Béatrice, additional, Jamet, Karine, additional, Cervera, Ludovic, additional, Mendez-Bermudez, Aaron, additional, Poncet, Delphine, additional, Grataroli, Renée, additional, de Rodenbeeke, Claire T’kint, additional, Salvati, Erica, additional, Rizzo, Angela, additional, Zizza, Pasquale, additional, Ricoul, Michelle, additional, Cognet, Céline, additional, Kuilman, Thomas, additional, Duret, Helene, additional, Lépinasse, Florian, additional, Marvel, Jacqueline, additional, Verhoeyen, Els, additional, Cosset, François-Loïc, additional, Peeper, Daniel, additional, Smyth, Mark J., additional, Londoño-Vallejo, Arturo, additional, Sabatier, Laure, additional, Picco, Vincent, additional, Pages, Gilles, additional, Scoazec, Jean-Yves, additional, Stoppacciaro, Antonella, additional, Leonetti, Carlo, additional, Vivier, Eric, additional, and Gilson, Eric, additional

Published
2013
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35. Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma.

Author

Pagnuzzi-Boncompagni, Marina, Picco, Vincent, Vial, Valérie, Planas-Bielsa, Victor, Vandenberghe, Ashaina, Daubon, Thomas, Derieppe, Marie-Alix, Montemagno, Christopher, Durivault, Jérôme, Grépin, Renaud, Martial, Sonia, Doyen, Jérôme, Gavard, Julie, and Pagès, Gilles

Subjects
*IN vitro studies, *DRUG approval, *NEOVASCULARIZATION inhibitors, *BLOOD-brain barrier, *ANTINEOPLASTIC agents, *GLIOMAS, *BRAIN tumors, *BENZAMIDE, *CELL lines, *DRUG toxicity
Abstract

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. 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. [ABSTRACT FROM AUTHOR]

Published
2022
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36. Linking JNK Activity to the DNA Damage Response

Author

Picco, Vincent and Pagès, Gilles

Abstract

The activity of c-Jun N-terminal kinase (JNK) was initially described as ultraviolet- and oncogene-induced kinase activity on c-Jun. Shortly after this initial discovery, JNK activation was reported for a wider variety of DNA-damaging agents, including ?-irradiation and chemotherapeutic compounds. As the DNA damage response mechanisms were progressively uncovered, the mechanisms governing the activation of JNK upon genotoxic stresses became better understood. In particular, a recent set of papers links the physical breakage in DNA, the activation of the transcription factor NF-?B, the secretion of TNF-a, and an autocrine activation of the JNK pathway. In this review, we will focus on the pathway that is initiated by a physical break in the DNA helix, leading to JNK activation and the resultant cellular consequences. The implications of these findings will be discussed in the context of cancer therapy with DNA-damaging agents.

Published
2013
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