cblc137 and Medulloblastoma

Topics: Animals; Apoptosis; Carbazoles; Cell Proliferation; Cerebellar Neoplasms; DNA-Binding Proteins; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; High Mobility Group Proteins; Humans; Medulloblastoma; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Prognosis; Smoothened Receptor; Transcriptional Elongation Factors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Medulloblastoma (MB) is a malignant pediatric brain tumor with a poor prognosis. Post-surgical radiation and cisplatin-based chemotherapy have been a mainstay of treatment, which often leads to substantial neurocognitive impairments and morbidity, highlighting the need for a novel therapeutic target to enhance the sensitivity of MB tumors to cytotoxic therapies. We performed a comprehensive study using a cohort of 71 MB patients' samples and pediatric MB cell lines and found that MB tumors have elevated levels of nucleosome remodeling FACT (FAcilitates Chromatin Transcription) complex and DNA repair enzyme AP-endonuclease1 (APE1). FACT interacts with APE1 and facilitates recruitment and acetylation of APE1 to promote repair of radiation and cisplatin-induced DNA damage. Further, levels of FACT and acetylated APE1 both are correlate strongly with MB patients' survival. Targeting FACT complex with CBL0137 inhibits DNA repair and alters expression of a subset of genes, and significantly improves the potency of cisplatin and radiation in vitro and in MB xenograft. Notably, combination of CBL0137 and cisplatin significantly suppressed MB tumor growth in an intracranial orthotopic xenograft model. We conclude that FACT complex promotes chemo-radiation resistance in MB, and FACT inhibitor CBL0137 can be used as a chemo-radiation sensitizer to augment treatment efficacy and reduce therapy-related toxicity in high-risk pediatric patients.

Topics: Adolescent; Adult; Animals; Carbazoles; Child; Child, Preschool; Cisplatin; DNA Damage; DNA Repair; DNA-(Apurinic or Apyrimidinic Site) Lyase; DNA-Binding Proteins; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Heterografts; High Mobility Group Proteins; Histone Chaperones; Humans; Male; Medulloblastoma; Mice; Transcriptional Elongation Factors; Young Adult

Medulloblastoma (MB) is the most common malignant pediatric brain tumor that can be categorized into four major molecular subgroups. Group 3 MB with MYC amplification (MYCamp-G3-MB) has been shown to be highly aggressive and exhibited worst prognosis, indicating the need for novel effective therapy most urgently. A few epigenetic targeted therapeutic strategies have recently been proven to effectively treat preclinical models of MYCamp-G3-MB, including BET inhibition, HDAC inhibition and SETD8 inhibition, unveiling a promising direction for further investigation. In this study, we carried out systemic bioinformatic analyses of public-available MB datasets as well as functional genomic screening datasets of primary MYCamp-G3-MB lines to search for other potential therapeutic targets within epigenetic modulators. We identified SSRP1, a subunit of histone-chaperone FACT complex, to be the top drug target candidate as it is highly cancer-dependent in whole-genome CRISPR-Cas9 screening across multiple MYCamp-G3-MB lines; significantly upregulated in MYCamp-G3-MB compared to normal cerebellum and most of the rest MB subtypes; its higher expression is correlated with worse prognosis; and it has a blood-brain-barrier penetrable targeted drug that has entered early phase human clinical trials already. Then we utilized RNA-interference approach to verify the cancer-dependency of SSRP1 in multiple MYCamp-G3-MB lines and further confirmed the therapeutic efficacy of FACT-targeted curaxin drug CBL0137 on treating preclinical models of MYCamp-G3-MB in vitro and in vivo, including an orthotopic intracranial xenograft model. Mechanistically, transcriptome analyses showed CBL0137 preferentially suppressed cell-cycle and DNA-repair related biological processes. Moreover, it selectively disrupted transcription of MYC and NEUROD1, two critical oncogenic transcription factors of MYCamp-G3-MB, via depleting FACT complex from their promoter regions. In summary, our study demonstrates FACT-targeted CBL0137 works effectively on treating MYCamp-G3-MB, presenting another promising epigenetic-targeted therapeutic strategy against the most devastating form of MB.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Carbazoles; Cell Cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; DNA Repair; DNA-Binding Proteins; Epigenesis, Genetic; Gene Amplification; Gene Expression Regulation, Neoplastic; High Mobility Group Proteins; Humans; Medulloblastoma; Mice, Nude; Otx Transcription Factors; Prognosis; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc; Transcription, Genetic; Transcriptional Elongation Factors; Transcriptome