Graduation Date

Summer 7-30-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Daryl J. Murry

Second Advisor

Sidharth Mahapatra

Third Advisor

Paul C. Trippier

Fourth Advisor

Aaron M. Mohs

Abstract

Group 3 medulloblastoma is the most aggressive subgroup of medulloblastoma, a common pediatric brain tumor, and a major cause of cancer-related mortality. It is characterized by MYC amplification, high metastatic rate, poor prognosis, and the absence of targeted therapies. Current standard of care encompasses surgical resection, irradiation, and chemotherapy, which are associated with long-term adverse effects in survivors. Development of novel or repurposed agents that produce therapeutic brain concentrations with a favorable safety profile is required to improve the therapeutic outcomes of patients with Group 3 medulloblastoma. The overarching aim of this study was to apply the principles of model-informed drug development by integrating in vitro and in vivo pharmacokinetics, toxicity, metabolomics, and physiologically-based pharmacokinetic modeling to expedite the development of Group 3 medulloblastoma therapies.

The first objective was to characterize the preclinical pharmacokinetics of Ni1, a novel putative B7-H3 inhibitor. Ni1 demonstrated favorable physiological and metabolic stability, high brain partitioning, and acceptable tolerability in mice, supporting its continued preclinical development. Targeted metabolomic profiling demonstrated that Ni1 significantly dysregulated multiple amino acid pathways and the tricarboxylic acid cycle, providing mechanistic insights into the cytotoxic mechanism of Ni1 in a MYC-amplified Group 3 medulloblastoma cell line.

The second objective of this research was to quantify brain penetration of two well-established drugs, artesunate and nortriptyline hydrochloride, repurposed for brain malignancies. Pharmacokinetic and maximum tolerated dose studies established brain exposure and tolerability of artesunate, informing future dose-optimization studies, while nortriptyline hydrochloride produced therapeutic brain concentrations at safe doses. A mechanistic physiologically-based pharmacokinetic model of nortriptyline revealed that sustained therapeutic brain concentrations can be achieved in mice with a wide therapeutic window. Translation to humans demonstrated that therapeutically relevant brain exposure is viable with currently approved human doses.

Collectively, this work integrated experimental pharmacology and computational modeling to establish a pharmacokinetic and translational framework for evaluating both novel and repurposed therapeutics for Group 3 medulloblastoma. It demonstrates the utility of model-informed drug development principles in accelerating drug development of therapies in this understudied malignancy.

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