Targeting of the ELR+CXCL/CXCR1/2 Pathway Is a Relevant Strategy for the Treatment of Paediatric Medulloblastomas.
Manon Penco-CampilloClément MolinaPatricia PirisNouha SoufiManon CarréMarina Pagnuzzi-BoncompagniVincent PiccoMaeva DufiesCyril RoncoRachid BenhidaSonia MartialGilles PagèsPublished in: Cells (2022)
Medulloblastoma (MB) is the most common and aggressive paediatric brain tumour. Although the cure rate can be as high as 70%, current treatments (surgery, radio- and chemotherapy) excessively affect the patients' quality of life. Relapses cannot be controlled by conventional or targeted treatments and are usually fatal. The strong heterogeneity of the disease (four subgroups and several subtypes) is related to innate or acquired resistance to reference treatments. Therefore, more efficient and less-toxic therapies are needed. Here, we demonstrated the efficacy of a novel inhibitor (C29) of CXCR1/2 receptors for ELR+CXCL cytokines for the treatment of childhood MB. The correlation between ELR+CXCL/CXCR1/2 expression and patient survival was determined using the R2: Genomics Analysis and Visualization platform. In vitro efficacy of C29 was evaluated by its ability to inhibit proliferation, migration, invasion, and pseudo-vessel formation of MB cell lines sensitive or resistant to radiotherapy. The growth of experimental MB obtained by MB spheroids on organotypic mouse cerebellar slices was also assayed. ELR+CXCL/CXCR1/2 levels correlated with shorter survival. C29 inhibited proliferation, clone formation, CXCL8/CXCR1/2-dependent migration, invasion, and pseudo-vessel formation by sensitive and radioresistant MB cells. C29 reduced experimental growth of MB in the ex vivo organotypic mouse model and crossed the blood-brain barrier. Targeting CXCR1/2 represents a promising therapeutic strategy for the treatment of paediatric MB in first-line treatment or after relapse following conventional therapy.
Keyphrases
- cell migration
- emergency department
- intensive care unit
- mouse model
- end stage renal disease
- immune response
- signaling pathway
- chronic kidney disease
- minimally invasive
- poor prognosis
- early stage
- induced apoptosis
- newly diagnosed
- drug delivery
- oxidative stress
- free survival
- single cell
- prognostic factors
- cell proliferation
- case report
- blood brain barrier
- endoplasmic reticulum stress
- white matter
- subarachnoid hemorrhage
- radiation induced
- surgical site infection