Bibbò, Francesca (2024) Targeting Group3 Medulloblastoma by the Anti‑PRUNE‑1 and Anti‑LSD1/KDM1A Epigenetic Molecules. [Tesi di dottorato]

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Abstract

Medulloblastoma (MB) is a highly malignant childhood brain tumor. Group3 MB (Gr3 MB) is considered to have the most metastatic potential and tailored therapies for Gr3 MB are currently lacking. Gr3 MB is driven by PRUNE-1 amplification or overexpression. Here in, we found that PRUNE-1 is transcriptionally regulated by the lysine demethylase LSD1/KDM1A. This study aimed to investigate the therapeutic potential of inhibiting both PRUNE-1 and LSD1/KDM1A with selective inhibitors AA7.1 and SP-2577, respectively. We found that the pharmacological inhibition has a substantial efficacy on targeting the metastatic axis driven by PRUNE-1 (PRUNE-1-OTX2-TGFβ-PTEN) in Gr3 MB. By RNA-seq transcriptomic features in Gr3 MB primary cells we provide evidence that the combination of AA7.1 and SP-2577 positively affects the neuronal commitment and the activation of cytotoxic components of the tumor microenvironment (TME). We have also identified the impairing action on the mitochondrial metabolism and consequently the oxidative phosphorylation (OXPHOS), thus depriving tumors cells of an important source of energy. Furthermore, by overlapping the genomic mutational signatures through WES analyses with RNA-seq data, we propose here that the combination of these two small molecules can be used as a second line treatment in advanced therapeutics against Gr3 MB. Our study demonstrates that the usage of PRUNE-1 and LSD1/KDM1A inhibitors in combination represent a novel therapeutic approach for Gr3 MB treatment.

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