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Triptolide and its prodrug Minnelide target high-risk MYC-amplified medulloblastoma in preclinical models
Jezabel Rodriguez-Blanco, … , Nagi G. Ayad, David J. Robbins
Jezabel Rodriguez-Blanco, … , Nagi G. Ayad, David J. Robbins
Published June 17, 2024
Citation Information: J Clin Invest. 2024;134(15):e171136. https://doi.org/10.1172/JCI171136.
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Research Article Oncology

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

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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 data set that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor 5-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.

Authors

Jezabel Rodriguez-Blanco, April D. Salvador, Robert K. Suter, Marzena Swiderska-Syn, Isabel Palomo-Caturla, Valentin Kliebe, Pritika Shahani, Kendell Peterson, Maria Turos-Cabal, Megan E. Vieira, Daniel T. Wynn, Ashley J. Howell, Fan Yang, Yuguang Ban, Heather J. McCrea, Frederique Zindy, Etienne Danis, Rajeev Vibhakar, Anna Jermakowicz, Vanesa Martin, Christopher C. Coss, Brent T. Harris, Aguirre de Cubas, X. Steven Chen, Thibaut Barnoud, Martine F. Roussel, Nagi G. Ayad, David J. Robbins

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Figure 3

Triptolide acts on MYC to attenuate G3 MB growth.

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Triptolide acts on MYC to attenuate G3 MB growth.
(A) HD:MB03 cells were...
(A) HD:MB03 cells were treated with 10 nM triptolide, followed by RNA-seq and gene set enrichment analyses (n = 3). Heatmap displays triptolide-regulated gene expression hallmarks, with an arrow indicating MYC targets. (B) The Cavalli et al. 2017 data set was analyzed to correlate MYC targets hallmark expression with G3 MB patient survival using log-rank (Mantel-Cox) tests. (C) DepMap gene dependency analyses predicted G3 MB cell dependency of genes downregulated by triptolide in the L1000 triptolide transcriptional response signature in Figure 1A. Arrow highlights MYC. (D) G3 MB cells were treated with triptolide for 24 hours, and MYC expression was quantified by RT-qPCR (n = 3). Values were analyzed using 1-way ANOVA followed by Dunnett’s post hoc test. (E) Lysates of G3 MB cultures exposed to triptolide were immunoblotted for the indicated proteins. (F) mG3-2929 cells were electroporated with HA-MYC 72 hours prior to 50 nM triptolide treatment. Cell viability was assessed by MTT reduction 48 hours later, while MYC levels were measured by immunoblotting 72 hours after electroporation (n = 3). (G) mG3-2929 cells were transfected for 48 hours with MYC-targeting siRNA, scramble siRNA (siSC), or GFP control, and then treated with 50 nM triptolide. Cell viability was assessed by MTT reduction 48 hours later, and MYC levels were measured by immunoblotting 72 hours after transfection (n = 3). (H) SHH-MB47 cells received MYC vector via electroporation 72 hours prior to exposure to 50 nM triptolide. Cell viability was measured using CellTiter-Glo assay 48 hours later. MYC levels were assessed in similarly electroporated cells exposed to 100 nM triptolide for 16 hours (n = 3). Images of representative immunoblots are shown. Unless otherwise indicated, all results are presented as mean ± SEM of data normalized to DMSO, where statistical significance was assessed using 1-way ANOVA followed by Newman-Keuls post hoc test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

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