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Research Update From Dr. Richard Lu at Cincinnati Children’s

Research Update From Dr. Richard Lu at Cincinnati Children’s

TeamConnor Childhood Cancer Foundation research grant update from Dr. Richard Lu at Cincinnati Children’s. Dr. Lu shared the following, “ We would like to express our sincerest gratitude to your unwavering support for our research. Your funding support has allowed us to gain new insights and innovations that will have a lasting impact on malignant brain tumors in children. We will continue to work tirelessly to honor your faith in us and to make a meaningful difference in fighting childhood cancer.”

Medulloblastoma is the most common brain tumor in childhood. Despite the current standard of care with multimodal therapy including surgery, conventional radiotherapy, and chemotherapy, a significant proportion of surviving patients suffer from tumor recurrence and serious treatment-related adverse events, both of which are significant barriers to effective treatment of MB. Patients with subtype 3 medulloblastoma often relapse, suffer metastasis, and eventually die from the disease after treatment. Targeted therapies are currently lacking for these aggressive tumors, in part due to a lack of complete understanding of the mechanisms of tumorigenesis and the clinical significance of genetic alterations. 

By analyzing recurrent genetic alterations in patients, we have identified and characterized a tumor suppressor gene called CTDNEP1 that is most frequently mutated in group 3 medulloblastomas. Mutations or low expression levels of CTDNEP1 are associated with poor patient outcomes. We found that CTDNEP1 mutations lead to activation of the cancer-promoting gene MYC, induce loss of the tumor suppressor p53 and genomic alterations to promote transformation of brain progenitor cells. Furthermore, we identified a dual inhibition strategy that simultaneously targets the oncogene MYC and the cell survival regulator CHEK1 for the treatment of aggressive group 3 medulloblastoma. 

When mice bearing tumor cells with high levels of MYC were treated with MYC and CHEK1 inhibitors, tumor growth was suppressed and the animals survived longer, overcoming the treatment-resistance that would normally circumvent monotherapy. Thus, our study has identified a potent tumor suppressor and a potential vulnerability for the future treatment of aggressive medulloblastoma. The research, supported by a TeamConnor grant, is now published in the journal Nature Communications (1).


Luo, Z., D. Xin, Y. Liao, K. Berry, S. Ogurek, F. Zhang, L. Zhang, C. Zhao, R. Rao, X. Dong, H. Li, J. Yu, Y. Lin, G. Huang, L. Xu, M. Xin, R. Nishinakamura, J. Yu, M. Kool, S. M. Pfister, M. F. Roussel, W. Zhou, W. A. Weiss, P. Andreassen, and Q. R. Lu. 2023. Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability. Nature Communications 14: 762.