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.
Funding Information
  • Rally Foundation (20CDN46)
  • V Foundation for Cancer Research (V2022-008)
  • Vince Lombardi Cancer Foundation (N/A)
  • Monka Foundation (N/A)
  • American Cancer Society (IRG-19-137-20)
  • Instituto Nacional de Cancerología (T32 CA009686)
  • Southeastern Brain Tumor Foundation (N/A)
  • National Institute of Neurological Disorders and Stroke (R01NS110591,NS118023,K01NS119351)
  • Instituto Nacional de Cancerología (R00 CA241367)
  • Southern Regional Education Board (SC15321)
  • College of Graduate Studies, Medical University of South Carolina (Odyssey)
  • Hollings Cancer Center, Medical University of South Carolina (Lowvelo Graduate Fellowship)
  • Hollings Cancer Center, Medical University of South Carolina (Lowvelo Postdoctoral Fellowship)
  • Foundation for the National Institutes of Health (P30CA046934)
  • Instituto Nacional de Cancerología (CA-096832)
  • Instituto Nacional de Cancerología (CA-21765)
  • American Lebanese Syrian Associated Charities (N/A)
  • Alex's Lemonade Stand Foundation for Childhood Cancer (23-28298)

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