Date of Award

1-1-2020

Embargo Period

4-22-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell and Molecular Pharmacology and Experimental Therapeutics

College

College of Graduate Studies

First Advisor

Nathan G. Dolloff

Second Advisor

Scott Eblen

Third Advisor

Perry V. Halushka

Fourth Advisor

Eric Bartee

Fifth Advisor

Patrick Woster

Abstract

Effectively treating therapeutic resistant malignancies remains one of the greatest challenges that cancer researchers and clinicians face today. Intra-tumoral heterogeneity contributes to intrinsic and acquired genetic alterations that render tumor cells nonresponsive to single agent therapies. Adaptations to endoplasmic reticulum (ER) stress are a critical driver of tumorigenesis and a source of therapeutic resistance in tumors, as many malignancies suppress this mechanism for survival. Therefore, combination strategies that induce ER stress offer an approach for combating therapeutic resistant cancer. The studies outlined in this dissertation offer two novel synergistic therapeutic strategies: (1) pairing glutaminase inhibitor CB-839 with proteasome inhibitors (PI) in refractory multiple myeloma and (2) combining a novel class of protein disulfide isomerase (PDI) inhibitors with histone deacetylase (HDAC) inhibitors in solid tumors. The driving force behind both therapeutic anti-tumor strategies relies on amplified ER stress-induced apoptosis. Multiple myeloma cells resistant to PIs exhibit increased mitochondrial respiration driven by glutamine as the principle fuel source. We utilized CB-839 to target glutamine-induced respiration in PI resistant cells and found that CB-839 synergistically enhanced PI-induced ER stress and apoptosis. This was characterized by the robust expression of ER stress markers ATF4 and CHOP. Alternatively, PDI and HDAC inhibitor combinations induce ER stress in solid tumors. HDAC inhibitors are largely ineffective in solid tumors as single agents. We discovered that PDI inhibitors dramatically and synergistically enhanced the anti-tumor activity of HDAC inhibitors in a variety of preclinical models, specifically pancreatic cancer and glioblastoma. RNA-Seq coupled with gene silencing studies identified ATF3 as the driver of this anti-tumor synergy. ATF3 upregulation was initiated by PDI inhibitor-induced ER stress and then potentiated by HDAC inhibitor-induced chromatin remodeling. In summary, the data presented in this dissertation identify two novel combination regimens with ER stress-inducing targeted agents that elicit anti-tumor responses. These studies demonstrate key mechanistic roles for ER stress markers ATF3, ATF4, and CHOP in the synergistic strategies and most importantly, present a way to achieve unrealized anti-tumor responses in therapeutic resistant cancer.

Rights

All rights reserved. Copyright is held by the author.

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