Retinoid X receptor (RXR) agonists bind to and activate the nuclear receptor RXR, thereby regulating gene transcription relevant to cellular proliferation, apoptosis, cell cycle, immunity, and numerous other biological processes. RXR agonists have been explored as treatments for cancer, metabolic disorders, and neurodegenerative diseases, and one RXR agonist, bexarotene, has been FDA approved for the treatment of cutaneous T cell lymphoma (CTCL). Bexarotene has also been tested in clinical trials for lung and metastatic breast cancer, wherein subsets of patients responded despite advanced disease. By modifying structures of known rexinoids, we can improve potency and toxicity. We have previously developed an in vitro screening paradigm that predicts activity in vivo and tested a series of novel rexinoids using this system of assays. This thesis project tested newly synthesized RXR agonists in preclinical mouse models of breast and lung cancer, diseases that cause significant morbidity and economic burden in the United States and worldwide. These novel compounds, V-125 and MSU 42011, are efficacious and well tolerated in the MMTV-Neu model of HER2+ breast cancer and the A/J model of non-small cell lung cancer. To generate mechanistic hypotheses for the anti-tumor efficacy of these novel compounds, RNA sequencing data from treated MMTV-Neu tumors is contained herein. Enrichment analyses of several RXR agonists depicts unique gene expression profiles, with unifying themes of immunomodulatory activity and modification of adhesion molecules and extracellular matrix components. This data and validation data provided direction for future mechanistic studies on the biological, immune modulatory, and anti-tumor effects of these compounds. By studying the mechanisms of these compounds, we may gain insight into how best to design future RXR agonists and how to utilize these compounds in human disease.
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