Targeted Therapies for Improving the Treatment of Sonic Hedgehog and MYC Driven Medulloblastoma

Author

Bharti Sethi, University of Nebraska Medical CenterFollow

ORCID ID

0000-0001-5083-8117

Graduation Date

Spring 5-6-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dr. Ram I Mahato

Second Advisor

Dr. Jered Garrison

Third Advisor

Dr. Donald Coulter

Fourth Advisor

Dr. Kishor Bhakat

Abstract

The aim of this thesis to develop a novel potent dual inhibitor to target BDR4/PI3K and MDM2/ XIAP pathways to treat medulloblastoma. A series of new analogs were synthesized, characterized, and evaluated in vitro and in vivo using xenograft and orthotopic mouse models.

In Chapter 1 an overview of Blood brain barrier such as their components, physiology, current drug delivery system and nanomedicines to treat medulloblastoma.

Chapter 2 includes synthesis of new molecule MDP5, targeting both BRD4 and PI3K pathways. We used X-ray crystal structures and molecular modeling approach to confirm the interactions between MDP5 with BD domains from both BRD2 and BRD4, and molecular modeling for PI3K binding. We evaluated MDP5 efficacy in vitro and in vivo. Treatment of MB cells with MDP5 significantly decreased the cell migration from apical side to basolateral chamber in transwells and have ability to target tumor initiating and side population cells. Further, MDP5 showed significant reduction in tumor size in animal model with no sign of toxicity and prolonged animal survival.

Chapter 3 cover ups the synthesis of new molecule JW475A, a dual MDM2/XIAP dual inhibitor. Here, we evaluated MDP5 and JW475A in combination to simultaneous inhibition of BRD4/PI3K and MDM2/XIAP pathways. We determined their combination efficacy in vitro and in vivo. For example, Western Blot results showed that combination treatment target both pathways. The xenograft animal model showed significant decreased in tumor size in combination group at lower dose as compared to monotherapy groups.

Finally, chapter 4 summarizes the results of this thesis and gives suggestions for future research.

Comments

2023 Copyright, the authors

Recommended Citation

Sethi, Bharti, "Targeted Therapies for Improving the Treatment of Sonic Hedgehog and MYC Driven Medulloblastoma" (2023). Theses & Dissertations. 724.
https://digitalcommons.unmc.edu/etd/724