PO-013 A novel peptidomimetic targeting NRP1 increases radiosensitivity of medulloblastoma stem cells

Introduction: Medulloblastoma (MB) is the most common paediatric malignant brain tumour. Recurrences occur in more than 40% of cases and sequelae are very important due to aggressiveness of the treatments. Cancer stem cells (CSCs) generate tumours through the stem cell patterns of self-renewal and differentiation into multiple tumour cell types and have better DNA repair capability inducing tumour resistance to radiotherapy (RT) and chemotherapy. Neuropilin-1 (NRP1) is involved in the progression of MB and seems to be in relation with the differentiation state of cancer cells. Recent molecular research has provided a better understanding of tumour development for the purpose of more targeted treatments. MR438 is a new sugarbased peptidomimetic targeting NRP-1. Our first results showed that MR438 seemed to induce the differentiation of MB stem cells. The objectives were therefore to demonstrate the effect of MR438 on in vitro and in vivo radiosensitivity. Material and methods: DAOY, D283Med and D341Med cell lines were used for obtaining cancer stem cells by in vitro enrichment. Clonogenic assays were performed on MB stem cells exposed to 0, 2, 4, 6, 10 Gy of RT in combination with MR438. For in vivo experiments, xenografted nude mice with 3 subgroup tumours were treated by RT at 2 Gy x 5 days in combination with MR438 and compared to Tuftsin in 6 groups (control, MR438, Tuftsin, RT, RT +MR438, RT +Tuftsin, n=6). Tumour volume was measured by calliper until a maximum of 45 days post-treatment, and then tumours were removed at the set end-points for clonogenic assay and cell viability. Results and discussions: Inhibition of NRP-1 via MR438 increased radiosensitivity of CSC models especially at the dose of 2 Gy. The DMF2 were 0.74, 0.89 and 0.88 for DAOY, D283-Med and Med-D341 cells respectively. In heterotopic models, a significant improvement of tumours radiosensitivity was also observed in the MR438 +RT group by comparing RT alone or MR438 alone (p