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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 Article has an altmetric score of 142

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 5

Triptolide reduces tumor growth in G3 MB mouse models.

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Triptolide reduces tumor growth in G3 MB mouse models.
(A) mG3-2929 cell...
(A) mG3-2929 cells were implanted into mice 15 days before starting vehicle or triptolide (0.4 mg/kg, i.p., daily) dosing for 5 days. Tumor area was measured in ×2.5-magnified H&E-stained tissues (n = 5), and representative images of whole and H&E-stained (scale bars: 400 μm) brains are shown. (B) mG3-2929 cells were allowed to form tumors for 4 days prior to starting similar triptolide dosing. Tumor size was determined 12 days later by IVIS imaging (n = 5). (C) Similar cells were orthotopically implanted 15 days before starting vehicle or triptolide dosing (0.4 mg/kg, i.p., daily) for 5 days. Brain tumors were harvested and their lysates immunoblotted for MYC (n = 4). (D) Brain tumor tissues from mice similarly treated for 5 days were harvested and immunostained for the indicated proteins. Number of positive cells per field was quantified (MYC n = 3, Ki67/C-Casp3 n = 4). Representative images (scale bars: 50 μm) are shown. (E) mG3-2929 cells were orthotopically implanted 3 days before dosing mice with vehicle or triptolide (0.4 mg/kg, i.p., daily) for 21 days. Symptom-free survival was analyzed using log-rank (Mantel-Cox) tests (n = 10). (F) Displayed are whole and H&E-stained (scale bars: 400 μm) brains from a symptomatic mouse in the vehicle cohort, along with 2 representative animals that remained asymptomatic 20 days after the last vehicle-treated mouse was euthanatized. RFP signal and arrows indicate tumor presence. In all cases, brains were harvested 6 hours after the last injection. Unless otherwise indicated, all results are presented as mean ± SEM of data normalized to 1 vehicle-treated animal. Statistical significance, unless otherwise specified, was assessed using an unpaired, 1-tailed Student’s t test. *P < 0.05; **P < 0.01; ****P < 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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