MDB-27. A PRO-DRUG OF TRIPTOLIDE IN CLINICAL DEVELOPMENT ATTENUATES HIGH-RISK MEDULLOBLASTOMA GROWTH

Medulloblastoma (MB), the most common malignant brain tumor of childhood, is currently classified in four major subgroups. A natural compound used in Chinese medicine for centuries, triptolide, has been shown to have a potent antitumor activity, and the efficacy of one of its derivatives is being evaluated in the clinic. However, to date no preclinical data supports the use of triptolide for the treatment of patients with MB. Here, we performed bioinformatic analyses to predict which subgroup of medulloblastoma patients would more likely benefit from the use of triptolide, and validated its efficacy in series of ex vivo and in vivo mouse and human derived MB models. Correlation analyses identified Group 3 (G3) MB patients as the most prone to respond to triptolide treatment. Consistent with this prediction, triptolide attenuated the growth of G3 MB at lower doses than those classified as SHH subgroup, increasing symptom-free survival in G3 mouse MB models. Transcriptomic analyses revealed MYC signaling as the key downstream target of triptolide in MB cells. Importantly, a pro-drug of triptolide in clinical development, minnelide, similarly showed efficacy in mouse and human derived G3 in vivo MB models. Our findings highlight the potential of repurposing Minnelide to treat G3 MB patients. Due to their dismal prognosis, inclusion of G3 MB patients in future minnelide clinical trials should be considered.