Abstract B16: Dissecting MDM2 function in medulloblastoma pathogenesis

Treatment for medulloblastoma (MB), a tumor of the cerebellum, involves an aggressive regimen of surgical resection, radiation and adjuvant chemotherapy. Although the 5-year cure rate is over 50%, most children retain life-long side effects associated with treatment, including reduced intellect. There is an urgent need to develop multi-targeted therapeutic strategies that enhance the killing of MB tumor cells while sparing normal cells. As a critical component of the cellular response to stress, p53 function is required for the cytotoxic effects of many chemotherapeutics. As p53 mutations are relatively rare in MB, adjuvant chemotherapeutics that enhance p53 function may have a profound effect in MB. Indeed, we previously reported that pharmacological disruption of the interaction of p53 with its negative regulator, MDM2, potentiates cell killing in human medulloblastoma cells. In order to gain further insight into the role of MDM2 in MB pathogenesis, here we have used a combination of wild-type, null, and hypomorphic alleles of MDM2 to perturb the MDM2-p53 pathway in Ptch1+/- mice, a model of human Sonic hedgehog (Shh)-induced MB. Our studies demonstrate that a 70% reduction in the level of MDM2 abrogates the formation of preneoplastic lesions (PNLs) in the cerebellum of Ptch1+/- mice, thereby supporting a requirement for MDM2 in MB initiation. Significantly, even a modest ~50% reduction in the level of MDM2 was sufficient to decrease PNL formation in the Ptch1+/- cerebellum in two-fold. Although reduced in number, detailed histological analyses of PNLs at P21 revealed no difference in the size, proliferation or apoptosis of PNLs between Ptch1+/- mice expressing a wild-type or 50% reduced level of MDM2. Next, we examined granule neuron precursors (GNPs) in the external granule layer (EGL) at P7, the pool of cells from which PNLs are presumed to originate. Consistent with the partial deregulation of Shh signaling in Ptch1+/- mice, the Ptch1+/- EGL was more highly proliferative than that of wild-type mice. Importantly, we found that the enhanced proliferation of EGL cells afforded by loss of one Ptch1 allele was restored back to wild-type levels when the level of MDM2 is reduced. Additionally, a 50% in the level of MDM2 potentiates apoptosis and enhances the steady state level of p53SER15 in the EGL in Ptch1+/- mice as compared to control mice. Dysregulation of the MDM2-p53 and Sonic hedgehog (Shh)-Gli pathways are both implicated in the pathogenesis of human MB; however, no approach to date has yielded a detailed understanding of how crosstalk between these two important pathways contributes to the proliferation, survival, and differentiation of GNPs, the presumed cell of origin for some MB subtypes. Our prior studies placed MDM2 at a critical node between the growth inhibiting the p53 pathway and the growth-promoting Shh-Gli pathway in normal cerebellar development. New work presented here further suggests that MDM2 is required for MB tumorigenesis to prevent p53 activation, which may in turn function to counteract deregulated Shh-mediated proliferation in the tumor initiating cell population. The coordinate regulation of these two important pathways may provide a mechanism to sustain tumor-promoting levels of Shh-Gli signaling without activating the tumor-suppressing functions of p53. By nature of its requirement in MB tumorigenesis, MDM2 may provide an important therapeutic target for boosting the efficacy of current MB treatments. Citation Format: Susan M. Mendrysa, Reem Malek. Dissecting MDM2 function in medulloblastoma pathogenesis. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B16.