Identifying a novel therapeutic target in Sonic Hedgehog medulloblastoma Restricted; Files Only

Wei, Yun (Fall 2018)

Permanent URL: https://etd.library.emory.edu/concern/etds/8w32r6672?locale=en
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Abstract

Medulloblastomas are the most common malignant pediatric brain tumors. The World Health Organization classified medulloblastomas into four molecular subgroups, including WNT-activated, SHH-activated TP53-mutant, SHH-activated TP53-wildtype, and non-WNT/SHH (also known as Group 3 and Group 4) in 2016. SHH-activated medulloblastomas have been well established, most of which harbor the aberrant driver Sonic Hedgehog signaling. However, the cure rate has reached a plateau over the past decade, due to the underrepresented integration of molecular discoveries into the stratification system or treatment protocols. Moreover, the lack of targeted therapy leads to the over-treatment of some patients, and the inadequacy to cure some other patients. This underscores the necessity to identify novel therapeutic targets for these patients. Even within SHH medulloblastomas, the intra-subgroup heterogeneity hinders the development of a “one-for-all” drug. Therefore, my research project focuses on 1) untangling the intra-subgroup heterogeneity of SHH medulloblastomas in respect of age demographics, signaling crosstalk, the tumor microenvironment compositions, and the possible epigenetics attributions, and 2) identifying I2PP2A as a novel therapeutic target for SHH medulloblastoma patients harboring wildtype TP53. We summarized the recent findings in SHH medulloblastoma research utilizing mouse models, patient samples, and the implications of these discoveries in guiding future stratification or treatment for SHH medulloblastoma patients. We postulated that the more refined stratification system and more tailored treatment protocols would benefit SHH medulloblastoma patients in the future, considering the intra-subgroup heterogeneity of this disease. Furthermore, we showed that I2PP2A, inhibitor 2 of protein phosphatase 2A, could be a potential target, which can be inhibited to restore TP53 function. In a SHH medulloblastoma mouse model, we tested the hypothesis that I2PP2A upregulates p-MDM2S166 by suppressing PP2A dephosphorylation activity, and that the subsequent accumulation of p-MDM2S166 degrades wildtype p53. We also demonstrated that targeting I2PP2A caused tumor cell death through inhibiting p-MDM2S166 and restoring p53 activity in both SHH medulloblastoma mouse model and patient-derived cell lines. We hope to facilitate improvements in refining current stratification and treatment protocols by illustrating the tumor heterogeneity and by identifying a novel therapeutic target for a subset of SHH medulloblastoma patients.

Table of Contents

Chapter 1.  Introduction 

1.1   Medulloblastoma

1.1.1    Medulloblastoma overview

1.1.2   Sonic-hedgehog activated medulloblastoma

1.1.3   Challenges in treating SHH medulloblastoma patients

1.2   p53 and SHH medulloblastoma

1.2.1   TP53 mutations in SHH medulloblastoma

1.2.2   p53 deficiency as a “second-hit” in promoting SHH medulloblastoma

1.2.3   The aberrant regulators of p53 in SHH medulloblastoma

1.3   I2PP2A in SHH medulloblastoma

1.3.1   PP2A as a possible MDM2 suppressor

1.3.2   The role of oncoprotein I2PP2A/SET in cancers

1.3.3   Hypothesis: I2PP2A compromises wildtype p53 in SHH medulloblastoma

1.4   Dissertation goals

1.4.1   Untangling the tumor heterogeneity of SHH medulloblastoma

1.4.2   Investigating the interaction of I2PP2A-p53 in SHH medulloblastoma

Chapter 2.  Untangling tumor heterogeneity in Sonic Hedgehog medulloblastomas

2.1   Introduction

2.2   Intra-subgroup heterogeneity of SHH medulloblastoma

2.3   Aberrant signaling crosstalk

2.4   Epigenetics

2.5   Tumor microenvironment

2.6   Conclusions

Chapter 3.  p53 Function is Compromised by Inhibitor 2 of Phosphatase 2A in Sonic Hedgehog Medulloblastoma

3.1   Introduction

3.2   Materials and Methods

3.3   Results

3.4   Discussion

Chapter 4.  Preliminary data of I2PP2A characterization

4.1   The oncogenic role of I2PP2A in vivo

4.2   I2PP2A and MDM2 during cerebellar development

4.3   The possible upstream regulator of I2PP2A protein stabilization

4.4   The role of p53 and p-AKT post-irradiation

Chapter 5.  Summary and Future Directions

5.1   Summary

5.1.1   Treatment options to target heterozygous SHH medulloblastomas

5.1.2   I2PP2A as a possible target in TP53 wildtype SHH medulloblastoma patients

5.2   Future directions

5.2.1   I2PP2A in SHH medulloblastoma patients

5.2.3   Implications of TP53 in radiation therapy for SHH medulloblastoma patients

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