Dataset Information

Triptolide and its pro-drug Minnelide target high-risk MYC amplified medulloblastoma in preclinical models.

ABSTRACT: Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic dataset that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor five-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB patients.

SUBMITTER: Rodriguez-Blanco J

PROVIDER: S-EPMC11290968 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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Triptolide and its prodrug Minnelide target high-risk MYC-amplified medulloblastoma in preclinical models.

Rodriguez-Blanco Jezabel J Salvador April D AD Suter Robert K RK Swiderska-Syn Marzena M Palomo-Caturla Isabel I Kliebe Valentin V Shahani Pritika P Peterson Kendell K Turos-Cabal Maria M Vieira Megan E ME Wynn Daniel T DT Howell Ashley J AJ Yang Fan F Ban Yuguang Y McCrea Heather J HJ Zindy Frederique F Danis Etienne E Vibhakar Rajeev R Jermakowicz Anna A Martin Vanesa V Coss Christopher C CC Harris Brent T BT de Cubas Aguirre A Chen X Steven XS Barnoud Thibaut T Roussel Martine F MF Ayad Nagi G NG Robbins David J DJ

The Journal of clinical investigation 20240617 15

Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic data se ...[more]

PMID: 38885332

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Project description: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.

Dataset Information

Triptolide and its pro-drug Minnelide target high-risk MYC amplified medulloblastoma in preclinical models.

Publications

Triptolide and its prodrug Minnelide target high-risk MYC-amplified medulloblastoma in preclinical models.

Similar Datasets

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