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posted on 2023-12-07, 14:20 authored by William Echavidre, Jérôme Durivault, Célia Gotorbe, Thays Blanchard, Marina Pagnuzzi, Valérie Vial, Florian Raes, Alexis Broisat, Rémy Villeneuve, Régis Amblard, Nicolas Garnier, Cécile Ortholan, Marc Faraggi, Benjamin Serrano, Vincent Picco, Christopher Montemagno In vivo measurement of integrin-αvβ3 expression using SPECT/MRI dual-modality. A, Representative coronal views of MRI (bottom), SPECT (center), and fused SPECT/CT/MRI of HD-MB03 (left) and DAOY (right) tumors at 1 hour postinjection of 99mTc-RAFT-RGD. B,In vivo quantification of 99mTc-RAFT-RGD tumor uptake from SPECT images. Results are expressed as tumor-to-cerebellum ratios. C, Autoradiography on 20 µm tumor-containing cerebellum slices (top) and staining of adjacent slices by Crystal Violet. D, Autoradiographic image quantification of 99mTc-RAFT-RGD uptake in HD-MB03 and DAOY tumor lesions. Results are expressed as tumor-to-cerebellum ratios. Key: *, P < 0.05; **, P < 0.01 versus HD-MB03.
Funding
Governement of the principality of Monaco
Fondation Flavien
GEMLUC
History
ARTICLE ABSTRACT
Medulloblastoma is one of the most prevalent solid tumors found in children, occurring in the brain's posterior fossa. The standard treatment protocol involves maximal resection surgery followed by craniospinal irradiation and chemotherapy. Despite a long-term survival rate of 70%, wide disparities among patients have been observed. The identification of pertinent targets for both initial and recurrent medulloblastoma cases is imperative. Both primary and recurrent medulloblastoma are marked by their aggressive infiltration into surrounding brain tissue, robust angiogenesis, and resistance to radiotherapy. While the significant role of integrin-αvβ3 in driving these characteristics has been extensively documented in glioblastoma, its impact in the context of medulloblastoma remains largely unexplored. Integrin-αvβ3 was found to be expressed in a subset of patients with medulloblastoma. We investigated the role of integrin-αvβ3 using medulloblastoma-derived cell lines with β3-subunit depletion or overexpression both in vitro and in vivo settings. By generating radioresistant medulloblastoma cell lines, we uncovered an increased integrin-αvβ3 expression, which correlated with increased susceptibility to pharmacologic integrin-αvβ3 inhibition with cilengitide, a competitive ligand mimetic. Finally, we conducted single-photon emission computed tomography (SPECT)/MRI studies on orthotopic models using a radiolabeled integrin-αvβ3 ligand (99mTc-RAFT-RGD). This innovative approach presents the potential for a novel predictive imaging technique in the realm of medulloblastoma. Altogether, our findings lay the foundation for employing SPECT/MRI to identify a specific subset of patients with medulloblastoma eligible for integrin-αvβ3–directed therapies. This breakthrough offers a pathway toward more targeted and effective interventions in the treatment of medulloblastoma.
This study demonstrates integrin-αvβ3’s fundamental role in medulloblastoma tumorigenicity and radioresistance and the effect of its expression on cilengitide functional activity.
