A medication initially designed for pancreatic cancer has shown promising results in extending symptom-free survival in experimental models of medulloblastoma, without displaying any adverse effects. Medulloblastoma, a malignant brain tumor that commonly affects children, has varying survival rates depending on its subtype. The most challenging form, known as Group 3, has historically offered the lowest survival rate, around 40%. This study specifically focused on this difficult subtype.
Dr. Jezabel Rodriguez Blanco, an assistant professor at MUSC Hollings Cancer Center and the Darby Children’s Research Institute at MUSC, spearheaded this research, which was featured in the Journal of Clinical Investigation.
Dr. Blanco’s investigation centered on the compound triptolide, extracted from a traditional Chinese medicinal vine, and its water-soluble precursor, Minnelide. A precursor is an inactive form of a drug that the body converts into its active state through biochemical processes.
The MYC gene, an oncogene that can initiate cancer, is abnormally active in about 70% of cancers and is present at significantly higher levels in Group 3 medulloblastoma than in other types. Targeting MYC has been challenging due to its complex nature.
Nonetheless, earlier research indicated that triptolide and its derivatives could effectively target MYC. During her time as a postdoctoral fellow at the University of Miami, Dr. Blanco was advised by her mentor, Dr. David Robbins, to investigate the drug’s potential against tumors with high MYC expression. This advice led Dr. Blanco to develop the research from the ground up, including acquiring cell lines and animal models and conducting experiments to test the drug’s efficacy.
Dr. Jezabel Rodriguez Blanco mentioned:
"The effectiveness in tumors with extra copies of MYC may be attributed to the drug working through two distinct mechanisms on this oncogene."
Dr. Jezabel Rodriguez Blanco initially secured a three-month grant designed for cancer center trainees to explore new ideas. Her lab then received a one-year grant from the Southeastern Brain Tumor Foundation in 2018, but there has been no additional funding specific to this project since then. Despite starting her faculty position at MUSC and shifting her primary research focus to the Sonic Hedgehog subgroup of medulloblastoma, Blanco continued to pursue her research on Group 3 medulloblastoma as a side project. Her dedication was driven by the promising results she observed with the drug triptolide and her desire to ensure that these findings were not overlooked.
Blanco acknowledged that uncovering the exact mechanism of action of triptolide has been particularly challenging due to its multiple effects. She suspects that additional mechanisms might still be undiscovered. She explained that the drug affects MYC gene expression by influencing RNA polymerase II activity and altering the protein’s stability. "The fact that it's working through two different mechanisms on this oncogene may explain why it's so effective in tumors that have extra copies of MYC," Blanco said. RNA polymerase II is crucial for transcribing DNA instructions into RNA, which then guides protein production within cells.
Despite the complexities involved in pinpointing the drug's specific mechanisms, Blanco observed significant efficacy. The drug Minnelide, a water-soluble prodrug of triptolide, was found to be 100 times more effective in Group 3 medulloblastoma tumors with additional MYC copies compared to Sonic Hedgehog tumors with normal MYC levels. Minnelide not only reduced tumor growth but also inhibited the spread of cancer cells to the leptomeninges, the delicate tissues covering the brain and spinal cord. Additionally, it enhanced the effectiveness of the chemotherapy drug cyclophosphamide, which is currently used in treatment protocols.
Blanco decided to proceed with publication rather than delay for a comprehensive manuscript. Her urgency was driven by the grim reality that children diagnosed with Group 3 medulloblastoma typically face a survival period of less than two years. "I could not hold these data any longer because it was working so well that it needed to be shared," Blanco explained. The promising results from preclinical models made it imperative to disseminate the findings promptly to potentially benefit children suffering from this aggressive cancer.
Minnelide is currently being tested in phase I and II clinical trials for various cancers, including pancreatic cancer, where it has shown some effectiveness. Blanco is hopeful that her research could lead to a clinical trial for children with Group 3 medulloblastoma.
In her publication, Blanco honors the memory of Insley Horn, a 9-year-old from Charleston who lost her battle with this aggressive brain tumor. Blanco emphasized that research remains the crucial tool for preventing such tragic losses, highlighting the vital role of continued investigation in the fight against cancer.
By: Medical University of South Carolina