ORCID ID
Graduation Date
Spring 5-4-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Cancer Research
First Advisor
Dalia ElGamal
MeSH Headings
Chronic Lympocytic Leukemia, Unfolded Protein Response, Drug Resistance, Therapeutic Research
Abstract
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by the accumulation of mature CD5+ B-cells in the peripheral blood, bone marrow, and secondary lymphoid tissues (e.g., spleen and lymph nodes).Despite the efficacy of front-line therapies, CLL is still an incurable disease, highlighting the need for development of novel therapeutics and further study of resistance mechanisms. Within the lymph node CLL tumor microenvironment (TME), there is an upregulation of gene signatures associated with B-cell receptor (BCR) and downstream nuclear factor kappa B (NF-κB) signaling compared to CLL cells found within the blood or bone marrow niches. Additionally, BCR signaling promotes aberrant protein synthesis, inducing the expression of oncogenic proteins (e.g., MYC and BCL2) and the upregulation of the unfolded protein response (UPR) to manage the increased cellular stress. Since malignant cells have higher basal levels of unfolded proteins, this poses a unique therapeutic window to combat CLL cell growth using pharmacological agents that induce the accumulation of misfolded proteins. In this dissertation, critical pathways such as BCR signaling, and downstream pathways/processes such as NF-κB signaling, cellular apoptosis, and the UPR in CLL were examined. Specifically, I elucidated the mechanism of action of a novel therapeutic agent, SpiD3, using in vitro and in vivo models of CLL. The integrated multi-omics and functional analyses revealed BCR signaling, NF-κB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR, inhibition of global protein synthesis, and induction of reactive oxygen species production in SpiD3-treated CLL cells. Translationally, I observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. In ibrutinib- and venetoclax-resistant CLL cells, SpiD3 retained its anti-leukemic effects, mirrored in reduced activation of key proliferative pathways like ERK and MYC. My preclinical findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including the UPR and NF-κB signaling, culminating in profound anti-tumor properties independent of TME stimuli.
Recommended Citation
Eiken, Alexandria, "Novel Spirocyclic Dimer (SpiD3) Displays Potent Preclinical Effects in Hematological Malignancies" (2024). Theses & Dissertations. 830.
https://digitalcommons.unmc.edu/etd/830
Frontiers (figure 2).png (37 kB)
AACR permission.pdf (334 kB)
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Included in
Animal Experimentation and Research Commons, Cancer Biology Commons, Hemic and Lymphatic Diseases Commons, Immune System Diseases Commons, Laboratory and Basic Science Research Commons, Molecular Biology Commons, Neoplasms Commons, Other Chemicals and Drugs Commons, Therapeutics Commons, Translational Medical Research Commons
Comments
2024 Copyright, the authors