Abstract B11: The oncogenic role of I2PP2A by inhibiting NME1 in SHH medulloblastoma

Abstract

Abstract Medulloblastoma is a pediatric brain tumor which arises in the cerebellum and is the most common childhood malignancy. The current standard of treatment for medulloblastoma (MB) is a combination of surgery, radiation and chemotherapy, which can cause lifelong side effects to MB survivors due to damage to the developing brain. Approximately 30% of human MB show aberrant Sonic Hedgehog (SHH) signaling and feature mutated SMO/PTCH1 or amplified GLI/NMYC, components of the SHH pathway. To study SHH-driven mitogenic and oncogenic signaling pathways, we use the NeuroD2-SmoA1 mouse model to investigate how downstream effectors of SHH signaling regulate cell proliferation in MB development. The NeuroD2-SmoA1 mouse closely recapitulates human SHH MB and bears constitutively active SMO in its cerebellum. The early onset and high incidence of tumors, and the adherence to human pathology make NeuroD2-SmoA1 mouse an efficient model for MB research. Utilizing this model, I have been focusing on the nuclear oncoprotein, I2PP2A, also known as endogenous inhibitor 2 of phosphatase 2A. I2PP2A has recently been proposed to be targeted in other malignant tumors such as leukemia, prostate, and lung cancers. However, whether I2PP2A play oncogenic roles in medulloblastoma has not been established yet. I found that I2PP2A protein is markedly elevated in mouse MB cytosol compared with neighboring normal cerebellum through histology and western blot approaches. In the efforts of searching molecules interacting with I2PP2A in cytoplasm, a non-metastasis marker, called NME1, stands out as the cytosol level of this protein also shows a strong induction. NME1 is a DNase that triggers cell death when tumor cells encounter the immune attack from the microenvironment. Based on the preliminary data, I hypothesize that I2PP2A sequesters NME1 in cytosol and inhibits the activation of this DNA nicking protein, thus prevents the MB cell death. My future plans are to determine the roles of I2PP2A and NME1 in tumorigenesis, test whether inhibiting I2PP2A can induce MB cell death mediated by NME1, and finally extrapolate this research to novel therapy design targeting I2PP2A in SHH medulloblastoma. Citation Format: Yun Wei, Anna Maria Kenney. The oncogenic role of I2PP2A by inhibiting NME1 in SHH medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B11.