Team 5

Design and application of innovative loco-regional Treatments in Glioblastoma

Team leader : Emmanuel Garcion

Emmanuel Garcion
Nantes-Angers Research Center for
Cancer and Integrated Immunology

Institut de Recherche et d’Ingénierie de la Santé - 4 Rue Larrey 49100 Angers

+33 (0) 2 44 68 85 43
emmanuel.garcion@univ-angers.fr

Project :

The two main limitations contributing to the failure of conventional therapy of certain solid tumors, among which glioblastoma is a typical example, are: i) treatment resistance ascribed to cell adaptation to environmental cues and ii) sub-optimal delivery of active principles. A major de facto objective of glioblastoma treatment is the exclusive eradication of tumor cells infiltrated in the central nervous system (CNS).

For more than 12 years our team has developed innovative micro and nanovectorisation-based strategies focusing on loco-regional delivery of anti-cancer medications in the CNS with demonstrated significant therapeutic benefit in preclinical models.

To further determine significance in humans and to better understand how these systems behave at the micro-nano-biological interface we now propose to focus on two main loco-regional approaches.

The first approach focuses on the development of novel nanovectorized internal radiation therapy combined with in situ radiosensitization. The choice of radiopharmaceuticals combined with the mode of delivery and intra-tumoral containment or targeting will be specifically addressed. The approach takes into account our new original data focusing on the nanoparticular targeting of the microRNA machinery involved in radioresistance. Milestones of this approach include the automation of the radiopharmaceutical formulation methods as well as the evaluation of the dosimetry correlated with biological responses.

The second approach focuses on implanting biointeractive “deposits” capable of interfering with tumor cell behavior (in terms of migration, differentiation and sensitivity to elimination signals) within the tumors or their resection cavities (perioperative surgery). This strategy is largely based on our expertise in the development of innovative formulations for releasing bioactive molecules (e.g. proteins). The aim of this project is to target cells to be eliminated and to modify their environment in order to attract and confine them in a controlled area for their destruction.

We expect to overcome key technological barriers limiting tissue homing and cellular and subcellular targeting of biomimetic vectors. We propose novel strategies for the targeting and elimination of radioresistant cells. The proposed work aims at developing relevant and optimized minimally invasive micro-nanomedicine strategies for the treatment of gliomas, as well as other solid tumors, by employing original and novel fundamental and technological approaches.

Emmanuel Garcion, DR Inserm

Lila Autier, PH ICO
Frank Boury, PU
Olivier Couturier, PU-PH
Florence Dumas-Giteau, MCU
François Hindré, MCU
Franck Lacoeuille, PU-PH
Jean-Michel Lemee, MCU-PH
Philippe Menei, PU-PH
Claudia Montero-Menei, MCU
Audrey Rousseau, PU-PH

Clémentine Lapoujade, Post-Doc

Sylvie Avril, TR Inserm
Laetitia Basset, IH CHU
Anne Clavreul, IH CHU
Marine Dion, TR CDD
Charlotte Roy, IE UA
Laurence Sindji, AI Inserm

Arthur Barcelos Ribeiro, PhD Student
Maël Bouillon, PhD Student
Alix Fontaine, PhD Student
Arianna Rinaldi, PhD Student

Clémentine Simon, Master 2
Mathis Barbotin, Master 2
 

2023

• R Molina-Peña, NH Ferreira, C Roy, L Roncali, M Najberg, S Avril, M Zarur, W Bourgeois, A Ferreirós, C Lucchi, F Cavallieri, F Hindré, G Tosi, G Biagini, F Valzania, F Berger, M Abal, A Rousseau, F Boury, C Alvarez-Lorenzo, E Garcion. (2023). Implantable SDF-1α-Loaded Silk Fibroin Hyaluronic Acid Aerogel Sponges as an Instructive Component of the Glioblastoma Ecosystem: Between Chemoattraction and Tumor Shaping into Resection Cavities. Acta Biomater. 173, 261–282.
• I Ottonelli, A Bighinati, E Adani, F Loll, R Caraffi, MA Vandelli, F Boury, G Tosi, JT Duskey, V Marigo, B Ruozi. (2023). Optimization of an Injectable Hydrogel Depot System for the Controlled Release of Retinal-Targeted Hybrid Nanoparticles. Pharmaceutics. 15 (1), 25.
• A Bikfalvi, CA da Costa, T Avril, JV Barnier, L Bauchet, L Brisson, PF Cartron, H Castel, E Chevet, H Chneiweiss, A Clavreul, B Constantin, V Coronas, T Daubon, M Dontenwill, F Ducray, N Entz-Werlé, D Figarella-Branger, I Fournier, JS Frenel, M Gabut, T Galli, J Gavard, G Huberfeld, JP Hugnot, A Idbaih, MP Junier, T Mathivet, P Menei, D Meyronet, C Mirjolet, F Morin, J Mosser, ECJ Moyal, V Rousseau, M Salzet, M Sanson, G Seano, E Tabouret, A Tchoghandjian, L Turchi, FM Vallette, S Vats, M Verreault, T Virolle. (2023). Challenges in Glioblastoma Research: Focus on the Tumor Microenvironment. Trends Cancer. 9 (1), 9–27.

2022

• C Roy, S Avril, C Legendre, B Lelièvre, H Vellenriter, S Boni, Jérôme C, C Guillet, Y Guilloux, M Chérel, F Hindré, E Garcion. (2022). A role for Ceruloplasmin in the control of human glioblastoma cell responses to radiation. BMC Cancer. 2;22(1):843.
• Alzial G, Renoult O, Paris F, Gratas C, Clavreul A, Pecqueur C. (2022). Wild-type isocitrate dehydrogenase under the spotlight in glioblastoma. Oncogene. 41(5):613-621.
• Sourty B, Dardaud LM, Bris C, Desquiret-Dumas V, Boisselier B, Basset L, Figarella-Branger D, Morel A, Sanson M, Procaccio V, Rousseau A. (2022). Mitochondrial DNA copy number as a prognostic marker is age-dependent in adult glioblastoma. Neurooncol Adv. 4(1):vdab191.
• Chuzeville, L; Boury, F; Duday, D; Moretto, E; Anand, R; Thomann, JS, (2022). Eco-friendly processes for the synthesis of amorphous calcium carbonate nanoparticles in ethanol and their stabilisation in aqueous media. Green Chem., 24, 1270-1284

2021

• R Molina-Peña, M Haji Mansor, M Najberg, JM Thomassin, B Gueza, C Alvarez-Lorenzo, E Garcion, C Jérôme, F Boury. (2021). Nanoparticle-containing electrospun nanofibrous scaffolds for sustained release of SDF-1α. International Journal of Pharmaceutics, 610 121205.
• V Simion, C Loussouarn, Y Laurent, L Roncali, D Gosset, F Reverchon, A Rousseau, F Martin, P Midoux, C Pichon, E Garcion*, P Baril*. (2021). LentiRILES, a miRNA-ON Sensor System for Monitoring the Functionality of miRNA in Cancer Biology and Therapy. RNABiology, 8, NO. S1: 198–214. *Equivalent contributions.
• D Séhédic, L Roncali, N Buchtova, S Avril, A Djoudi, M Chérel, F Boury, F Lacoeuille, F Hindré, E Garcion. (2021). Rapamycin-loaded lipid nanocapsules induce selective inhibition of the mTORC1-signaling pathway in glioblastoma cells. Frontiers in Bioengineering and Biotechnology Nanobiotechnology, 8: 602998.
• Ah-Pine, F., Casas, D., Menei, P., Boisselier, B., Garcion, E., and Rousseau, A. (2021). RNA-sequencing of IDH-wild-type glioblastoma with chromothripsis identifies novel gene fusions with potential oncogenic properties. Translationnal Oncology 4 :100884.
• M Haji Mansor, E Garcion, B Ramalapa, N Buchtova, C Toullec, M Aucamp, J Le Bideau, F Hindré, A Dube, C Alvarez-Lorenzo, M Galleni, C Jérôme, F Boury. (2021). Polymer-based protein delivery systems for loco-regional administration. Book Chapter11, Green Synthesis in Nanomedicine and Human Health, By Richard Glover, CRC Press Taylor & Francis group, pp.249-270.

2020

• Najberg, M., Haji Mansor, M., Taillé, T., Bouré, C., Molina-Peña, R., Boury, F., Cenis, J.L., Garcion, E. *, and Alvarez-Lorenzo, C.* (2020). Aerogel sponges of silk fibroin, hyaluronic acid and heparin for soft tissue engineering: Composition-properties relationship. Carbohydrate Polymers 237, 116107. *Equivalent contributions.
• Clavreul, A., Menei, P. (2020). Mesenchymal Stromal-Like Cells in the Glioma Microenvironment: What Are These Cells? Cancers (Basel) 12(9):2628.
• Oddone, N., Boury, F., Garcion, E., Grabrucker, A.M., Martinez, M.C., Da Ros, F., Janaszewska, A., Forni, F., Vandelli, M.A., Tosi, G., Forni, F., Ruozi, B. Duskey, J. T. (2020). Synthesis, Characterization, and In Vitro Studies of an Reactive Oxygen Species (ROS)-Responsive Methoxy Polyethylene Glycol-Thioketal-Melphalan Prodrug for Glioblastoma Treatment. Front Pharmacol 11, 574.
• Simion, V., Henriet, E., Juric, V., Aquino, R., Loussouarn, C., Laurent, Y., Martin, F., Midoux, P., Garcion, E., Pichon, C., and Baril, P. (2020). Intracellular trafficking and functional monitoring of miRNA delivery in glioblastoma using lipopolyplexes and the miRNA-ON RILES reporter system. J Control Release 327, 429-443.
• Grégoire, H., Roncali, L., Rousseau, A., Chérel, M., Delneste, Y., Jeannin, P., Hindré, F., and Garcion, E. (2020). Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma. Front Pharmacol 11, 368.
• Ugur, D., Sottile, V., Montero-Menei, C.N., Boury, F., Zelzer, M. (2020). Relating polymeric microparticle formulation to prevalence or distribution of fibronectin and poly-d-lysine to support mesenchymal stem cell growth. Biointerphases 15, 041008.

2019

• Bailly, C., Vidal, A., Bonnemaire, C., Kraeber-Bodere, F., Chérel, M., Pallardy, A., Rousseau, C., Garcion, E., Lacoeuille, F., Hindré, F., Valable, S., Bernaudin, M., Bodet-Milin, C., Bourgeois, M. (2019). Potential for Nuclear Medicine Therapy for Glioblastoma Treatment. Front Pharmacol 10, 772.
• Autier, L., Clavreul, A., Cacicedo, M.L., Franconi, F., Sindji, L., Rousseau, A., Perrot, R., Montero-Menei, C.N., Castro, G.R., Menei, P. (2019). A new glioblastoma cell trap for implantation after surgical resection. Acta Biomater 84, 268-279.
• Lajous, H., Lelievre, B., Vauleon, E., Lecomte, P., Garcion, E. (2019). Rethinking Alkylating(-Like) Agents for Solid Tumor Management. Trends Pharmacol Sci 40, 342-357.
• Clavreul, A., Pourbaghi-Masouleh, M., Roger, E., Menei, P. (2019). Nanocarriers and nonviral methods for delivering antiangiogenic factors for glioblastoma therapy: the story so far. Int J Nanomedicine 14, 2497-2513.
• Clavreul, A., Soulard, G., Lemée, J.M., Rigot, M., Fabbro-Peray, P., Bauchet, L., Figarella-Branger, D., Menei, P., and network, F.G.B. (2019). The French glioblastoma biobank (FGB): a national clinicobiological database. Journal of translational medicine 17, 133.
• Dardaud, L.M., Bris, C., Desquiret-Dumas, V., Boisselier, B., Tabouret, E., Mokhtari, K., Figarella-Branger, D., Rousseau, A.*, Procaccio, V.* (2019). High mitochondrial DNA copy number is associated with longer survival in young patients with glioblastoma. Neuro Oncol. 21(8): 1084–1085. *Equivalent contributions.
• Lepareur, N., Lacoeuille, F., Bouvry, C., Hindré, F., Garcion, E., Chérel, M., Noiret, N., Garin, E., Knapp, F.F.R., Jr. (2019). Rhenium-188 Labeled Radiopharmaceuticals: Current Clinical Applications in Oncology and Promising Perspectives. Frontiers in medicine 6, 132.
• Najberg, M., Haji Mansor, M., Boury, F., Alvarez-Lorenzo, C., Garcion, E. (2019). Reversing the Tumor Target: Establishment of a Tumor Trap. Front Pharmacol 10, 887.
• André, E.M., Delcroix, G.J., Kandalam, S., Sindji, L., and Montero-Menei, C.N. (2019). A Combinatorial Cell and Drug Delivery Strategy for Huntington's Disease Using Pharmacologically Active Microcarriers and RNAi Neuronally-Committed Mesenchymal Stromal Cells. Pharmaceutics 11: 526.
• Ah-Pine, A Rousseau. Les tumeurs du système nerveux central. Encyclopédie Médico-Chirurgicale, Elsevier Masson, (2019).

2018

• Haji Mansor, M., Najberg, M., Contini, A., Alvarez-Lorenzo, C., Garcion, E., Jerome, C., Boury, F. (2018). Development of a non-toxic and non-denaturing formulation process for encapsulation of SDF-1alpha into PLGA/PEG-PLGA nanoparticles to achieve sustained release. Eur J Pharm Biopharm 125, 38-50.
• Boisselier, B., Dugay, F., Belaud-Rotureau, M.A., Coutolleau, A., Garcion, E., Menei, P., Guardiola, P., Rousseau, A. (2018). Whole genome duplication is an early event leading to aneuploidy in IDH-wild type glioblastoma. Oncotarget 9, 36017-36028.
• Anthiya, S., Griveau, A., Loussouarn, C., Baril, P., Garnett, M., Issartel, J.P., Garcion, E. (2018). MicroRNA-Based Drugs for Brain Tumors. Trends in Cancer 4, 222-238.
• Lajous, H., Riva, R., Lelievre, B., Tétaud, C., Avril, S., Hindré, F., Boury, F., Jérome, C., Lecomte, P., Garcion, E. (2018). Hybrid Gd(3+)/cisplatin cross-linked polymer nanoparticles enhance platinum accumulation and formation of DNA adducts in glioblastoma cell lines. Biomaterials Science 6, 2386-2409.
• Clavreul, A., Roger, E., Pourbaghi-Masouleh, M., Lemaire, L., Tétaud, C., Menei, P. (2018). Development and characterization of sorafenib-loaded lipid nanocapsules for the treatment of glioblastoma. Drug delivery 25, 1756-1765.
• Dreyfus, M., EL-ATIFI, M., Court, M., Bidart, M., Coutton, C., Leclech, C., Ballester, B., Garcion, E., Bouamrani, A., Berger, F., R., Wion, D. (2018). Reprogramming glioma cell cultures with retinoic acid: Additional arguments for reappraising the potential of retinoic acid in the context of personalized glioma therapy. Glioma 1, 66-78.
• Lemée, J.M., Clavreul, A., Aubry, M., Com, E., de Tayrac, M., Mosser, J., Menei, P. (2018). Integration of transcriptome and proteome profiles in glioblastoma: looking for the missing link. BMC molecular biology 19, 13.

2017

• Kandalam, S., Sindji, L., Delcroix, G.J., Violet, F., Garric, X., Andre, E.M., Schiller, P.C., Venier-Julienne, M.C., des Rieux, A., Guicheux, J., Montero-Menei, C. N. (2017). Pharmacologically active microcarriers delivering BDNF within a hydrogel: Novel strategy for human bone marrow-derived stem cells neural/neuronal differentiation guidance and therapeutic secretome enhancement. Acta Biomater 49, 167-180.
• Ramalapa, B., Crasson, O., Vandevenne, M., Gibaud, A., Garcion, E., Cordonnier, T., Galleni, M., Boury, F. (2017). Protein-polysaccharide complexes for enhanced protein delivery in hyaluronic acid templated calcium carbonate microparticles. J Mat Chem B 5, 7360-7368.
• Sehedic, D., Chourpa, I., Tétaud, C., Griveau, A., Loussouarn, C., Avril, S., Legendre, C., Lepareur, N., Wion, D., Hindré, F., Davodeau, F., Garcion, E. (2017). Locoregional Confinement and Major Clinical Benefit of (188)Re-Loaded CXCR4-Targeted Nanocarriers in an Orthotopic Human to Mouse Model of Glioblastoma. Theranostics 7, 4517-4536
• Boisselier, B., De Carli, E., Rousseau, A. (2017). Molecular alterations in pediatric gliomatosis cerebri are similar to those in less invasive forms of pediatric diffuse glioma. J Neurooncol 133, 217-219.
• Cikankowitz, A., Clavreul, A., Tetaud, C., Lemaire, L., Rousseau, A., Lepareur, N., Dabli, D., Bouchet, F., Garcion, E., Menei, P., Couturier, O., Hindré, F. (2017). Characterization of the distribution, retention, and efficacy of internal radiation of (188)Re-lipid nanocapsules in an immunocompromised human glioblastoma model. J Neurooncol 131, 49-58.
• Clavreul, A., Pourbaghi-Masouleh, M., Roger, E., Lautram, N., Montero-Menei, C.N., Menei, P. (2017). Human mesenchymal stromal cells as cellular drug-delivery vectors for glioblastoma therapy: a good deal? J Exp Clin Cancer Res 36, 135.
• El Ayoubi, R., Boisselier, B., Rousseau, A. (2017). Molecular landscape of pediatric diffuse intrinsic pontine gliomas: about 22 cases. J Neurooncol 134, 465-467.

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