Abstract 2468: Overcoming the leptomeningeal seeding of medulloblastoma by targeting HSP70

Abstract

Abstract Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor and the development of leptomeningeal dissemination (LM seeding) through the cerebrospinal fluid (CSF) circulation is a major cause of treatment failure. We have previously established the MB LM seeding mouse model. In this study, we aimed to determine molecules that can target seeding (metastatic) cells by analyzing their specific genetic and functional characteristics. Methods: Seeding and non-seeding cells were isolated and cultured, respectively, and microarray analysis was carried out. Proliferation and wound-healing assays were performed through the HCS system, and viability, migration and adhesion assays were accomplished. In addition, the therapeutic effect of the selected inhibitor was analyzed by region of interest (ROI) analysis of bioluminescence in vivo. Results: The gene expression and functional characteristics of the successfully obtained seed cells and non-seed cells were compared and analyzed. Differentially expressed genes (DEGs) analysis indicated that heat shock protein 70 (Hsp70) was in the highest rank in seeding cells, and pathway enrichment analysis revealed that the metabolism was the main pathway enriched in seeding cells. Proliferation of seeding cells was slower than that of non-seeding cells, but there was no significant difference in viability. Notably, the wound-healing of seeding cells was delayed, but the adhesion ability on collagen was higher. Among the six HSP70 inhibitors, VER155008 was efficiently sensitive to seeding cells, and suppression of expression of MRP proteins along with HSP70 was also confirmed. In addition, it was observed that the treatment of VER155008 reduced seeding through the spinal cord in vivo. Conclusion: Our study suggests that VER15008 can be a promising treatment option, targeting LM seeding of MB. Citation Format: Seung Ah Choi, Saehim Ha, Hee-Young Lee, Joo Whan Kim, Jin Chul Paeng, Ji Hoon Phi. Overcoming the leptomeningeal seeding of medulloblastoma by targeting HSP70 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2468.