Abstract A52: Investigation of p53 restoration therapy in a mouse model of pineoblastoma

Abstract

Abstract Background: Pineoblastoma is a malignant childhood tumor with poor outcomes. We have previously characterized a mouse model of pineoblastoma induced by transgenic expression of Cyclin D1 in a p53 null background. We showed that Cyclin D1 expression in the setting of intact p53 results in pineal hyperplasia, but no onset of invasive tumors, reminiscent of pineal enlargement seen in a subset of children with RB haploinsufficiency. In the setting of p53 loss, pineoblastoma occurs with 100% penetrance. We now investigated the role of p53 restoration therapy in prevention and treatment of pineoblastoma using this mouse model. Results: We found that restoration of p53 in mouse pre-malignant proliferating pineal tumors results in tumor prevention, shown by effective cell cycle exit and induction of cellular senescence, a tumor suppressor mechanism. Conversely, p53 reactivation in established malignant pineal tumors had no effect cell proliferation, unless paired with DNA damaging therapy. The response to p53 restoration did not correlate with levels of p19Arf expression. Interestingly, in premalignant lesions, p53 restoration was associated with secondary amplification of MAPK signaling and induction of p19Arf expression. Subsequent inactivation of p53 after senescence resulted in diffuse re-entry into the cell cycle and rapid tumor progression. Evaluation of a panel of human supratentorial primitive neuroectodermal tumors showed low activity of the p53 pathway, while only one of 6 tumors had p53 deletion or mutation. Conclusion: Our data shows that, in a mouse model of Cyclin D1-driven pineoblastoma, restoration of p53 has different effects in premalignant versus invasive pineal tumors, where it may need to be paired with DNA damaging agents for effective tumor suppression. Furthermore, p53 activation may need to be continually sustained in such lesions undergoing senescence. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene seems to be intact but the pathway inactive in the majority of examined tumors. Citation Format: Mohammad Harajly, Hassan Zalzali, Zafar Nawaz, Raya Saab. Investigation of p53 restoration therapy in a mouse model of pineoblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A52.