All ETDs from UAB

Advisory Committee Chair

Christopher D Willey

Advisory Committee Members

G Yancey Gillespie

Anita B Hjelmeland

Marry-Ann Bjornsti

Markus Bredel

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Glioblastoma (GBM; grade IV astrocytoma) is the most common primary adult brain malignancy and remains incurable despite tremendous advances in our understanding of this heterogeneous disease. In this dissertation, we explore the challenges encountered in the treatment of GBM and discuss a promising new therapeutic approach gleaned from studies of the phospholipid binding “effector” domain (ED) of the protein Myristoylated alanine-rich protein C kinase substrate (MARCKS). Following an introduction to central nervous system (CNS) tumors and the grading of diffuse gliomas, we explain how recent advancements to our understanding of the cellular and molecular composition of CNS tu-mors, and the tumor microenvironment, has offered renewed hope for the successful utili-zation of targeted therapies. The vast majority of GBM possesses oncogenic signaling resulting from hyperac-tivity of receptor tyrosine kinases (RTKs), phosphatidylinositol 3-kinase (PI3K) or loss of the tumor suppressor phosphatase and tensin homolog (PTEN), resulting in the dysregula-tion of phospholipid signaling. MARCKS ED sequesters the common phospholipid sub-strate of this dysregulated pathway, so we explore MARCKS potential growth and radiation sensitizing effects in GBM, and the impacts ED phosphorylation has on its tumor-suppressing effects. Next, we explore the utility of a cell-penetrant ED mimetic (MED2) for the treatment of GBM. We find MARCKS overexpression to suppress GBM growth inhibition and enhance radiation sensitivity, and that ED phosphorylation blocks these effects. Additionally, we find MED2 is potently cytotoxic against molecularly classified GBM patient-derived xenografts (PDX) with low toxicity in normal human astrocytes (NHA). Utilizing a new imaging cytometry platform, we revealed MED2 selectively binds and ac-cumulates into GBM over NHAs resulting in a robust calcium influx and rapid membrane permeabilization that is resistant to caspase inhibition. We hypothesize this selective binding of MED2 results from differences in the phospholipid composition of GBM plasma mem-branes compared to healthy cells and propose this cytolytic cell death is potentially immu-nogenic suggesting MED2 can be valuable as an adjuvant therapy to immunomodulating therapies. Overall, we show that MARCKS can regulate the progression of GBM and find MED2 to have multiple desirable therapeutic effects against GBM worthy of additional in-vestigation. Keywords: Glioblastoma, MARCKS, Effector domain, Peptide therapeutic.

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