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

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 2

G3 MB cultures have an enhanced response to triptolide.

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G3 MB cultures have an enhanced response to triptolide. (A) The Cavalli ...
(A) The Cavalli et al. 2017 data set was used to compare the expression of MYC in G3 MB patients versus the other MB subgroups. Expression data were analyzed using an unpaired, 1-tailed Student’s t test. (B) MYC levels were assessed by immunoblotting in 3 G3 and 3 SHH MB cultures. (C) G3 and SHH MB cells were incubated with increasing concentrations of triptolide for 48 hours before assaying cell viability using an MTT reduction assay. EC50 values were calculated using nonlinear regression analyses (G3 MB n = 4, SHH MB n = 3). (D) G3 and SHH MB cultures were exposed to the indicated concentrations of triptolide for 16 hours. Cell proliferation and apoptosis were assayed by EdU incorporation and cleaved Casp3 (C-Casp3) staining, respectively. Representative images (scale bars: 50 μm) are shown. (E) Quantification of the number of EdU-positive cells per field in similarly treated cultures (n = 3). (F) The number of C-Casp3–positive cells per field in similarly treated cultures was quantified (n = 3). Data presented as mean ± SEM. Data in E and F were normalized to DMSO and analyzed using 1-way ANOVA followed by Dunnett’s post hoc test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.