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

Abstract

Material and methods Several HCC cell lines were used to compare phenotypical features, susceptibility to platelets and drug-mediated effects. To determine effects on cancer cell features, in vitro cell growth and transwell invasion assays were performed. Furthermore, the underlying mechanism of a platelet-modulated drug response on the molecular level was explored. Results and discussions In HCC cells, the anti-proliferative potency of sorafenib was counteracted by platelet factors and the mesenchymal phenotype. However, resminostat alone and in combination with sorafenib effectively triggered an anti-proliferative response independently of platelets or the mesenchymal phenotype. Therefore, resminostat determined the antiproliferative response of the drug combination. Moreover, recent reports highlight HCC cell subpopulations which express cancer stem cell genes and harbour clonogenic growth and cell invasive capacities as critical for metastasis. Intriguingly, we found that platelets induced the cell-invasive capacity in HCC cells with detectable levels of several cancer stem cell markers and which featured a mixed epithelial-mesenchymal phenotype. Importantly, only the combination of resminostat with sorafenib, but not the mono-treatments, significantly reversed the platelet-induced cell invasion. Conclusion Our pre-clinical data provide evidence on how platelets mediate pro-tumorigenic effects and modulate the therapeutic response to the resminostat/sorafenib drug combination. Platelet factors negatively modulated the drug response to sorafenib. This was overcome by the anti-proliferative activities of resminostat. Importantly, providing an explanation for the clinical benefit of the combination therapy, the platelet-induced invasive capacity was reversed only by the combination of resminostat with sorafenib, but not the mono-treatments. 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 w...