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).

Publication:

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.