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A model for Group C Medulloblastoma induced by deletion of RB1 and p53 tumor suppressors

Eldad Zacksenhaus

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Canadian Institutes of Health Research (CIHR)
Medulloblastoma (MB) is a pediatric malignancy of the brain for which no good therapy is currently available. Patients are treated surgically, by radiation and by cytotoxic chemotherapy. Even when cure is achieved, the radiation treatment causes serious long-term side effects such as reduced cognitive functions. We shown that the RB1 pathway and p53 tumor suppressors are frequently disrupted in Group 3 MB, the most aggressive subtype. However, the cell-of-origin of Group 3 MB is not known and, until now, there has been no available mechanism to specifically delete genes in cells within the cerebellum that give rise to this disease. We found that WAP-Cre, a transgenic mouse strain used to delete genes in mammary epithelium, is expressed in the cerebellum and that combined inactivation of Rb and p53 with this deleter line induces brain tumors that resemble human Group 3 MB. We will identify and characterize the cell of origin of these aggressive tumors and search for therapeutic vulnerabilities.

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