ORCID ID
Graduation Date
Spring 5-4-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Cancer Research
First Advisor
Dalia El-Gamal, Ph.D.
Second Advisor
Jennifer Black, Ph.D.
Third Advisor
Sarah Holstein, M.D., Ph.D.
Fourth Advisor
Grinu Mathew, Ph.D.
Abstract
Chronic lymphocytic leukemia (CLL) develops through a combination of intrinsic genetic defects, constitutively active survival/proliferation signaling pathways, and complex microenvironment interactions. Redundant tumor microenvironment (TME) immuno-suppressive mechanisms and epigenetic maintenance of terminal T-cell dysfunction also greatly hinder anti-tumor T-cell responses in CLL. Small-molecule agents targeting the B-cell receptor (BCR) pathway and anti-apoptotic proteins alone or in combination with chemo-immunotherapy have revolutionized the management of CLL, yet there is still a significant need for novel therapeutic strategies to yield durable tumor elimination. Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that bind to acetyl-lysine residues on histones to regulate gene transcription. BET proteins, such as BRD4, have pleiotropic functions in normal biology and disease states. In CLL, BRD4 regulates key pathways contributing to pathogenesis (e.g., expression of MYC and BCR pathway components) and TME interactions, including T-cell function and differentiation. This work firstly evaluated the pre-clinical efficacy of novel small molecule inhibitors capable of concomitantly inhibiting BRD4 and BCR pathway components BTK and PI3K (SRX3305 and SRX3333) in CLL. These compounds specifically inhibit their molecular targets and are cytotoxic to CLL cells at low micro-molar doses, even in the presence of supportive TME stimuli and BTK inhibitor resistance. Furthermore, I found that a novel BET inhibitor (OPN-51107) alleviates immuno-suppressive networks in the CLL TME and repairs inherent T-cell defects. In pre-clinical models of CLL, OPN-51107 treatment reduced expression of immune inhibitory receptors, enhanced T-cell proliferation and effector function, shifted the T-cell transcription factor landscape, and altered CLL T-cell exhaustion-associated chromatin organization to promote a progenitor T-cell phenotype. At the beginning of the COVID-19 pandemic, I additionally evaluated the usage of BET inhibitors to combat SARS-CoV-2 infection. Apabetalone (RVX-208), a BET inhibitor approved for clinical use in cardiovascular disorders, was found to reduce expression of cell surface receptors involved in SARS-CoV-2 entry and inhibit SARS-CoV-2 infection akin to anti-viral agents. Collectively, these studies demonstrate the enormous potential of BET protein inhibition to be used as a component of treatment regimens for hematological malignancies, such as CLL, as well as non-oncology applications.
Recommended Citation
Smith, Audrey L., "Therapeutic Effects of BET Protein Inhibition in B-cell Malignancies and Beyond" (2024). Theses & Dissertations. 815.
https://digitalcommons.unmc.edu/etd/815
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Cancer Biology Commons, Hemic and Lymphatic Diseases Commons, Immune System Diseases Commons, Immunity Commons, Neoplasms Commons, Other Chemicals and Drugs Commons, Translational Medical Research Commons, Virus Diseases Commons
Comments
2024 Copyright, the authors