Online

Davidson, Cole Dakota

Cellular, Molecular, and Biomedical Sciences Program

2022

Ph. D.

Thyroid cancer is the most common endocrine malignancy, and the global incidence has increased rapidly over the past few decades. While differentiated thyroid cancers often respond to standard therapies, there are no durable long-term treatment options for anaplastic thyroid cancer (ATC). The limited treatment options highlight a need for a deeper understanding of the molecular signaling in these aggressive tumors for development of more effective therapies.Non-steroidal nuclear receptors, such as thyroid hormone receptors (TRs), are an emerging class of therapeutic targets and tumor suppressors in thyroid and other cancers.Loss of expression of the tumor suppressor thyroid hormone receptor beta (TRβ) is strongly associated with ATC. Here we report that reintroduction of TRβ and activation with the thyroid hormone triiodothyronine suppressed PI3K signaling in ATC cells. This pathway suppression was achieved via genomic mechanisms, including repressing RTK expression and increasing phosphoinositide and Akt phosphatase expression. Furthermore, the reintroduction and activation of TRβ in ATC cells enhanced the efficacy of the PI3K inhibitors LY294002 and buparlisib on cell viability, migration, and suppression of PI3K signaling. This novel mechanism of TRβ tumor suppression implies expression levels of TRβ may reveal tumor susceptibility to therapeutics that target PI3K signaling. A major consequence of PI3K-Akt signaling in cancer cells is an increased rate of cell metabolism. Our previous study identified enhanced expression of glycogen metabolism genes in ATC cells, a metabolic process that has yet to be explored or targeted in thyroid cancer. While the impact of TRβ on systemic metabolism is well studied, there is little known on the tumor suppressor's role in cancer metabolism. Glycogen is an advantageous storage form of glucose for cancer cells to break down in times of low cellular energy or oxidative stress. Expression of the brain isoform of glycogen phosphorylase (PYGB) was found to be significantly upregulated in patient biopsy samples of thyroid cancer. In addition to inhibiting PI3K signaling, reintroduction of TRβ in ATC cells decreased expression of PYGB and cell migration inducing hyaluronidase (CEMIP), which regulates PYGB activation. We directly inhibited PYGB by repurposing the antidiabetic agent CP-91,149 (CP) to induce apoptosis and accumulation of glycogen and reactive oxygen species in ATC cells. CP also greatly enhanced the efficacy of sorafenib, a mainline MAPK signaling inhibitor used in ATC patients. Following our success with CP using in vitro models, we were encouraged to evaluate CP alone and in combination with sorafenib in vivo, especially since CP efficacy had yet to be demonstrated in a xenograft model. We show for the first time that CP dramatically blunts ATC tumor growth in vivo. CP was so effective as a single agent that there was no further efficacy observed in combination with sorafenib. This study presents promising clinical potential for targeting glycogen metabolism in ATC as well as other aggressive solid tumors. The data presented here not only establish glycogen metabolism as a novel metabolic process in ATC but uncover further TRβ-mediated mechanisms of tumor suppression in anaplastic thyroid cancer. In conclusion, the findings presented in this dissertation shed light onto the genomic mechanisms by which TRβ attenuates PI3K signaling and glycogen metabolism in ATC, potentially affording improved clinical outcomes in patients with anaplastic thyroid cancer or other solid tumors.