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Published on: June 13, 2019
Targeting Group 3 Medulloblastoma by the Anti-PRUNE-1 and Anti-LSD1/KDM1A Epigenetic Molecules
Francesca Bibbò1,2, Fatemeh Asadzadeh2,3, Angelo Boccia2
1Department of Molecular Medicine and Medical Biotechnological DMMBM, University Federico II of Naples, 80131 Naples, Italy.
Abstract:
Medulloblastoma (MB) is a highly malignant childhood brain tumor. Group 3 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. In this paper, we found that PRUNE-1 was transcriptionally regulated by lysine demethylase LSD1/KDM1A. This study aimed to investigate the therapeutic potential of inhibiting both PRUNE-1 and LSD1/KDM1A with the selective inhibitors AA7.1 and SP-2577, respectively. We found that the pharmacological inhibition had a substantial efficacy on targeting the metastatic axis driven by PRUNE-1 (PRUNE-1-OTX2-TGFβ-PTEN) in Gr3 MB. Using RNA seq transcriptomic feature data in Gr3 MB primary cells, we provide evidence that the combination of AA7.1 and SP-2577 positively affects neuronal commitment, confirmed by glial fibrillary acidic protein (GFAP)-positive differentiation and the inhibition of the cytotoxic components of the tumor microenvironment and the epithelial-mesenchymal transition (EMT) by the down-regulation of N-Cadherin protein expression. We also identified an impairing action on the mitochondrial metabolism and, consequently, oxidative phosphorylation, thus depriving tumors cells of an important source of energy. Furthermore, by overlapping the genomic mutational signatures through WES sequence analyses with RNA seq transcriptomic feature data, we propose in this paper that the combination of these two small molecules can be used in 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 represents a novel therapeutic approach for these highly aggressive metastatic MB tumors.
Insights
Targeting PRUNE-1 and LSD1/KDM1A with combined inhibitors shows promise for Group 3 medulloblastoma (Gr3 MB). This novel approach inhibits metastasis, promotes neuronal differentiation, and impairs tumor cell energy metabolism in advanced Gr3 MB.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Group 3 medulloblastoma (Gr3 MB) is a highly aggressive childhood brain tumor with significant metastatic potential.
- Current therapies for Gr3 MB are limited, highlighting the need for novel treatment strategies.
- PRUNE-1 amplification/overexpression drives Gr3 MB, and its transcriptional regulation by LSD1/KDM1A presents a therapeutic target.
Purpose of the Study:
- To investigate the therapeutic efficacy of simultaneously inhibiting PRUNE-1 and LSD1/KDM1A in Gr3 MB.
- To evaluate the impact of combined PRUNE-1 and LSD1/KDM1A inhibition on the metastatic axis and cellular processes in Gr3 MB.
Main Methods:
- Pharmacological inhibition of PRUNE-1 using AA7.1 and LSD1/KDM1A using SP-2577 in Gr3 MB models.
- RNA sequencing (RNA-seq) for transcriptomic analysis of primary Gr3 MB cells.
- Whole Exome Sequencing (WES) for genomic mutational signature analysis.
- Assessment of neuronal differentiation (GFAP), epithelial-mesenchymal transition (EMT markers), and mitochondrial metabolism.
Main Results:
- Combined inhibition effectively targeted the PRUNE-1-driven metastatic axis (PRUNE-1-OTX2-TGFβ-PTEN).
- Treatment promoted neuronal commitment and differentiation, inhibited EMT (down-regulation of N-Cadherin), and reduced tumor microenvironment cytotoxicity.
- Mitochondrial metabolism and oxidative phosphorylation were impaired, reducing tumor cell energy supply.
Conclusions:
- Combination therapy with PRUNE-1 and LSD1/KDM1A inhibitors offers a novel therapeutic strategy for metastatic Gr3 MB.
- This approach demonstrates potential as a second-line treatment for advanced Gr3 MB by targeting key oncogenic pathways and cellular functions.
- The findings support the development of dual-inhibitor therapies for aggressive medulloblastoma subtypes.
