Date of Completion

7-30-2019

Embargo Period

7-28-2024

Keywords

Blood cancer, chemotherapy, immunotherapy, tropolone, T cells

Major Advisor

Andrew Wiemer

Associate Advisor

Olga Vinogradova

Associate Advisor

Dennis L. Wright

Associate Advisor

Diane J. Burgess

Associate Advisor

Brian J. Aneskievich

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

This thesis focuses on identification and development of novel small molecule therapeutics for blood cancer. The studies presented herein examine two classes of novel compounds with different mechanisms: tropolones as chemotherapies (Chapters II and III) and phosphoantigens as immunotherapies (Chapters IV-VII).

A library of α-tropolone derivatives was tested for anti-proliferative effects on a panel of hematological malignancies demonstrating preference towards cells of T cell lineage. Through investigating different compounds, some structure activity relationships for compound potency were determined. As a class, the mechanism of action was reliant upon the caspase pathway, p53 regulation, Akt, mTor, and iron. The α-substituted tropolones upregulate DNA damage repair pathways leading to caspase-dependent apoptosis in malignant T lymphocytes.

Several phosphoantigen prodrugs were evaluated for ability to stimulate an anti-cancer response from the Vγ9Vδ2 T cells. As a class, the compounds can induce differentiation, proliferation, and cytokine (IFN-γ) production of Vγ9Vδ2 T cells. New models were developed to assess function, including a humanized xenograft mouse model and a firefly luciferase lysis assay. These assays show prodrugs can sensitize xenograft tumor cells to T cell lysis and display superior safety profile relative to bisphosphonates in mice.

Furthermore, phosphoantigens bind the internal domain of butyrophilin 3A1 (BTN3A1) in target cells. We demonstrated using nuclear magnetic resonance spectroscopy (NMR) that the juxtamembrane (JM) region experiences conformational rearrangement after ligand binding. Amino acids at positions 296 and 304 are involved. A strategy combining live cell chemical crosslinking and high performance liquid chromatography/mass spectrometry (LC/MS) was further used to identify other binding partners of the BTN3A1 extracellular domain.

Together, the studies described in this thesis advance our understanding of the structure activity relationships, the mechanisms of action, and the in vivo safety and efficacy, of these novel tropolones and phosphoantigens.

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