Recently, Nagendra Chaturvedi, PhD, and colleagues in the Pediatric Cancer Research Group (PCRG) published a manuscript titled “A Novel Combination Approach Targeting an Enhanced Protein Synthesis Pathway in MYC-driven (Group 3) Medulloblastoma,” in the journal Molecular Cancer Therapeutics.1 Dr. Chaturvedi participated in the following Q&A for the CHRI Research Bulletin.
Q: Your new article reports on bench research studying medulloblastoma. Briefly describe this cancer – how is it unique from a clinical or scientific perspective?
A: This manuscript describes the evaluation of a new therapeutic approach to the treatment of medulloblastoma, focusing on Group 3 disease, which has the worst prognosis. Medulloblastoma is the most common pediatric brain tumor and it arises in the cerebellum in the back part of the brain. This cancer is classified into four Groups depending on the molecular abnormalities of the tumor cells. Initial treatment involves surgery, radiation and chemotherapy which unfortunately fails to cure about a third of patients, especially those with Group 3 disease. Therapy also has significant side effects in survivors.
Q: What key questions were you trying to answer?
A: Group 3 tumors express the mTOR gene pathway that controls protein synthesis and regulates the MYC gene which is overexpressed in these tumors. The consequence is that Group 3 tumors have amplified protein synthesis, increased cell proliferation and survival factors that make them resistant to standard therapies, hence the poor survival outcomes. The MYC gene is large and complex, with many functions and is difficult to target directly. However, several small molecules have been developed recently that indirectly downregulate the MYC gene. The innovation of this project was to combine inhibitors of the mTOR pathway with these small molecule inhibitors of MYC and determine the effects on patient-derived medulloblastoma cell lines, including difficult to treat Group 3 tumors.
Q: What were your team’s main findings about medulloblastoma tumor formation?
A: Our studies showed that this combination of treatments downregulated MYC expression, reduced global protein synthesis and induced growth arrest and apoptosis (i.e. death of the tumor cells), particularly in Group 3 tumor cells. The treatment was then tested against human medulloblastoma cells growing under the skin of immunodeficient mice. The volume of such tumors can be measured regularly and the mice observed for toxicities. Tumor growth was slowed significantly, with no evidence of toxicities. In order to model the patient situation, the human tumor cells were then injected into the cerebellum of mice and the treatment administered, versus a placebo. The combination treatment significantly prolonged the survival of the mice, with no evidence of toxicities directly related to the treatment. Additionally, there is evidence that this treatment synergizes with chemotherapy, so it may be possible to achieve the same therapeutic endpoint with lower doses of chemotherapy and lower toxicities.
Q: What needs to happen next to keep making progress on the road to better treatments for medulloblastoma?
Overall, this new targeted small molecule approach to the treatment of group 3 medulloblastoma appears promising. The next challenge is to begin to translate this information to the clinic. This requires determination of optimal doses and scheduling of therapy, as well as more detailed analyses of toxicities that might need to be managed. These data will be employed to design a Phase I trial in patients. We are submitting grant requests to fund the collection of data to enable the design of a trial.
1. Chaturvedi, N. K., Kling, M. J., Griggs, C. N., Kesherwani, V., Shukla, M., McIntyre, E. M., Ray, S., Liu, Y., McGuire, T. R., Sharp, J. G., Band, H., Joshi, S. S., & Coulter, D. W. (2020). A Novel Combination Approach Targeting an Enhanced Protein Synthesis Pathway in MYC-driven (Group 3) Medulloblastoma. Molecular cancer therapeutics, molcanther.0996.2019. Advance online publication. https://doi.org/10.1158/1535-7163.MCT-19-0996
Q&A published May 19, 2020