Analysis Of The Therapeutic Mechanism Of Action Induced By Selective Activation Of Trβ In Anaplastic Thyroid Cancer

Thyroid cancer is the most common endocrine cancer. Papillary thyroid cancer (PTC) is the most common with generally a very good prognosis although treatment resistance and variants also occur. Follicular thyroid cancer (FTC) is less common yet like PTC, FTC is differentiated and has a good therapeutic response. Anaplastic thyroid cancer (ATC) is the most lethal endocrine cancer with no enduring treatments. ATC, which is undifferentiated, accounts for approximately 14-39% of deaths associated with thyroid cancer. ATC has poor prognosis with a survival of less than 9 months from diagnosis, thus urgently needing more combinations of targeted therapies. Two most abundant thyroid hormone receptor (TR) isoforms, TRα and TRβ, are nuclear receptors that mediate thyroid hormone action, activating different signaling pathways to regulate critical physiological processes. The natural ligand of TRs (3,5,3’-triiodo-L-thyronine, T3), acts on both isoforms. While the role of TRα in cancer development is not well defined, it is now well recognized that the nuclear transcription factor TRβ has tumor suppressing effect in thyroid, breast, and other cancers, with preliminary studies establishing that Sobetirome (or GC-1), a TRβ selective agonist, has the potential to alter tumorigenic phenotypes and inhibit tumor growth. It is hypothesized that modifying TRβ gene regulation will induce specific important physiological changes and reveal GC-1 mechanisms of action on ATC cells. The aim of this project is to conduct an integrated analysis of the therapeutic mechanism of action induced by selective activation of TRβ in both normal thyroid cells and aggressive thyroid cancer cells, through characterization of agonist-induced gene regulatory network and gene differential expression using RNA-seq, and how TRβ agonism affects chromatin accessibility using ATACseq. The results of these studies unveiled previously unknown additional tumor suppressors, upregulated by selective TRβ activation. Certain genes, such as TNFRSF9 and IGFBP4, have been shown to possess anti-tumor and apoptosis-enhancing effect in other cancer types. Transcription factor analysis of publicly available RNA-seq data from thyroid cancer patient tissues, using decoupleR, identified several novel transcription factors, associated with TRβ-mediated chromatin accessibility, including SP1 and the Krüppel-like factor family, which has been potentially linked with more aggressive thyroid cancer phenotypes. All of these bioinformatic analysis provide exploratory groundwork for future experiments that would validate these genes and transcription factors, before investigating their potential as therapeutic targets for anaplastic thyroid cancers.