Matching Items (12)
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- All Subjects: Cancer
- All Subjects: Bexarotene
- Creators: Compton, Carolyn
- Status: Published
Description
Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost the immune system. Bex has been shown to be effective in the treatment of multiple types of cancer, including lung cancer. However, the disadvantages of using Bex include increased instances of hypothyroidism and excessive concentrations of blood triglycerides. If an analog of Bex can be developed which retains high affinity RXR binding similar to the 9-cis retinoic acid while exhibiting less interference for heterodimerization pathways, it would be of great clinical significance in improving the quality of life for patients with CTCL. This thesis will detail the biological profiling of additional novel (Generation Two) analogs, which are currently in submission for publication, as well as that of Generation Three analogs. The results from these studies reveal that specific alterations in the core structure of the Bex "parent" compound structure can have dramatic effects in modifying the biological activity of RXR agonists.
ContributorsYang, Joanna (Author) / Jurutka, Peter (Thesis director) / Wagner, Carl (Committee member) / Hibler, Elizabeth (Committee member) / Barrett, The Honors College (Contributor)
Created2012-05
Description
Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated that bexarotene has a specific affinity for retinoid X receptors (RXR), which allows bexarotene to act as a ligand-activated-transcription factor and in return control cell differentiation and proliferation. Bexarotene targets RXR homodimerization to drive transcription of tumor suppressing genes; however, adverse reactions occur simultaneously when bound to other nuclear receptors. In this study, we used novel bexarotene analogs throughout 5 iterations synthesized in the laboratory of Dr. Wagner to test for their potency and ability to bind RXR. The aim of our study is to quantitatively measure RXR homodimerization driven by bexarotene analogs using a yeast two-hybrid system. Our results suggests there to be several compounds with higher protein activity than bexarotene, particularly in generations 3.0 and 5.0. This higher affinity for RXR homodimers may help scientists identify a compound that will minimize adverse effects and toxicity of bexarotene and serve as a better cancer treatment alternative.
ContributorsSeto, David Hua (Author) / Marshall, Pamela (Thesis director) / Wagner, Carl (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor) / School of Social and Behavioral Sciences (Contributor)
Created2015-05
Description
Cancer, a disease which affects many lives, has been the topic of interest for this research. Treatment options are often available to help lessen the effects of the disease and in regards to cutaneous T-cell lymphoma (CTCL), no cure currently exists. An FDA approved drug by the name of Bexarotene has been developed to provide chemotherapeutic effects within CTCL. Bexarotene has also been used in trials of breast cancer, lung cancer, glioblastoma multiforme and various neurodegenerative diseases. Yet the medication often causes serious side effects including hyperthyroidism, raised triglyceride levels and cutaneous toxicity. The focus of this research is to synthesize a hydroxylated analog compound of Bexarotene in efforts to produce a molecule that provides better chemotherapeutic effects while also lessening the various side effects caused. Synthesis of the molecule followed various organic chemistry techniques and reactions to create the final product. Melting point analysis, NMR and other various characterization data helped to confirm the synthesis of the intended molecule. Preliminary bioassay data results of the analog compound showed similar potency to that of Bexarotene. Further testing, however, will be required to determine the full pharmacokinetic profile of the molecule. Future direction of the research focuses on both further testing of the hydroxylated analog as well synthesizing newer analog compounds to find a molecule that can provide the best effects within cutaneous T-cell lymphoma and the various other diseases as well.
ContributorsMinasian, Ani Christina (Author) / Wagner, Carl (Thesis director) / Marshall, Pamela (Committee member) / School of Social and Behavioral Sciences (Contributor) / School of Mathematical and Natural Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
The ever-increasing importance of cancer and neurodegenerative diseases continues to grow as populations across the world are affected by death and aging. The vitamin A (RXR) and vitamin D (VDR) receptor pathways offer promising potential to aid in treatment of cancer and Alzheimer’s disease. This thesis discusses the potential application of novel analogs of Bexarotene (RXR agonist), MeTC7 (a new potent VDR antagonist), and vitamin D as possible therapeutics for cancer and Alzheimer’s disease.
ContributorsHong, Jennifer (Author) / Jurutka, Peter (Thesis director) / Wagner, Carl (Committee member) / Marshall, Pamela (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor)
Created2023-05
Description
Bexarotene is a Food and Drug administration (FDA)-approved therapeutic used in the treatment of cutaneous T-cell lymphoma (CTCL). However, bexarotene therapy causes significant side effects like hyperlipidemia and hypothyroidism due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. More recently bexarotene has shown promise to reverse neurodegeneration, improve cognition and decrease levels of amyloid- β in transgenic mice expressing familial Alzheimer’s disease (AD) mutations. Bexarotene is a high affinity ligand for the retinoid X receptor (RXR) that heterodimerizes with the liver- X- receptors (LXR) and with peroxisome proliferator-activated receptor-gamma (PPARϒ) to control cholesterol efflux, inflammation, and transcriptionally upregulates the production of apolipoprotein (ApoE) in the brain. Enhanced ApoE expression may promote clearance of soluble Aβ peptides from the brain and reduce Aβ plaques, thus resolving both amyloid pathology and cognitive deficits. The present study assessed the potential of bexarotene and a group of 62 novel rexinoids to bind and activate RXR using a series of biological assays and screening methods, including: 1) a mammalian two-hybrid system (M2H) and an 2) Retinoid X Receptor response element (RXRE)-mediated reporter assays in cultured human cells. Moreover, Liver X Receptor response element (LXRE)-mediated luciferase assays were performed to analyze the ability of the novel analogs to activate LXRE - directed transcription, and to induce ApoE messenger ribonucleic acid (mRNA) in U87 glial cells. Furthermore, the most potent analogs were analyzed via quantitative polymerase chain reaction (qPCR) to determine efficacy in modulating expression of two critical tumor suppressor genes, activating transcription factor 3 (ATF3) and early growth response 3 (EGR3). Results from these multiple assays indicate that the panel of RXR ligands contains compounds with a range of activities, with some analogs capable of binding to RXR with higher affinity than others, and in some cases upregulating ApoE expression to a greater extent than bexarotene. The data suggests that minor modifications to the bexarotene core chemical structure may yield novel analogs possessing an equal or greater capacity to activate RXR and may be useful as therapeutic agents against CTCL and Alzheimer’s disease.
ContributorsReshi, Sabeeha Mushtaq (Author) / Jurutka, Peter (Thesis advisor) / Wagner, Carl (Committee member) / Marshall, Pamela (Committee member) / Arizona State University (Publisher)
Created2023
Description
Cancer researchers have traditionally used a handful of markers to understand the origin of tumors and to predict therapeutic response. Additionally, performing machine learning activities on disparate data sources of varying quality is fraught with inherent bias. The Caris Life Sciences Molecular Database (CMD) is an immense resource for discovery as it contains over 215,000 molecular profiles of tumors with consistently gathered clinical grade molecular data along with immense amounts of clinical outcomes data. This resource was leveraged to generate two artificial intelligence algorithms aiding in diagnosis and one for therapy selection.
The Molecular Disease Classifier (MDC) was trained on 34,352 cases and tested on 15,473 unambiguously diagnosed cases. The MDC predicted the correct tumor type out of thirteen possibilities in the labeled data set with sensitivity, specificity, PPV, and NPV of 90.5%, 99.2%, 90.5% and 99.2% respectively when considering up to 5 predictions for a case.
The availability of whole transcriptome data in the CMD prompted its inclusion into a new platform called MI GPSai (MI Genomic Prevalence Score). The algorithm trained on genomic data from 34,352 cases and genomic and transcriptomic data from 23,137 cases and was validated on 19,555 cases. MI GPSai can predict the correct tumor type out of 21 possibilities on 93% of cases with 94% accuracy. When considering the top two predictions for a case, the accuracy increases to 97%.
Finally, a 67 gene molecular signature predictive of efficacy of oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer was developed - FOLFOXai. The signature was predictive of survival in an independent real-world evidence (RWE) dataset of 412 patients who had received FOLFOX/BV in 1st line and inversely predictive of survival in RWE data from 55 patients who had received 1st line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR=0.629, p=0.04 and FOLFOXIRI HR=0.483, p=0.02).
The Molecular Disease Classifier (MDC) was trained on 34,352 cases and tested on 15,473 unambiguously diagnosed cases. The MDC predicted the correct tumor type out of thirteen possibilities in the labeled data set with sensitivity, specificity, PPV, and NPV of 90.5%, 99.2%, 90.5% and 99.2% respectively when considering up to 5 predictions for a case.
The availability of whole transcriptome data in the CMD prompted its inclusion into a new platform called MI GPSai (MI Genomic Prevalence Score). The algorithm trained on genomic data from 34,352 cases and genomic and transcriptomic data from 23,137 cases and was validated on 19,555 cases. MI GPSai can predict the correct tumor type out of 21 possibilities on 93% of cases with 94% accuracy. When considering the top two predictions for a case, the accuracy increases to 97%.
Finally, a 67 gene molecular signature predictive of efficacy of oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer was developed - FOLFOXai. The signature was predictive of survival in an independent real-world evidence (RWE) dataset of 412 patients who had received FOLFOX/BV in 1st line and inversely predictive of survival in RWE data from 55 patients who had received 1st line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR=0.629, p=0.04 and FOLFOXIRI HR=0.483, p=0.02).
ContributorsAbraham, Jim (Author) / Spetzler, David (Thesis advisor) / Frasch, Wayne (Thesis advisor) / Lake, Douglas (Committee member) / Compton, Carolyn (Committee member) / Arizona State University (Publisher)
Created2020
Description
With cancer rates increasing and affecting more people every year, I felt it was important to educate the younger generation about the potential factors that could put them at risk of receiving a cancer diagnosis later in life. I thought that this was important to do because most students, especially in rural communities, are not taught the factors that increase your risk of getting cancer in the future. This leads to students not having the tools to think about the repercussions that their actions can have in their distant future in regard to their risk of getting cancer. I went to six schools throughout the valley and the White Mountains of Arizona with differing education levels and demographics to provide them with prevention strategies that they could implement into their daily lives to reduce their risk of getting cancer in the future. Some of the schools had curriculums that included cancer and some of the factors that increase your risk, while others never mention what is happening biologically when a person has cancer. I introduced factors such as no smoking or tobacco use, diet, exercise, sunscreen use, avoiding alcohol, and getting screened regularly. While at each school, I discussed the importance of creating these healthy habits while they are young because cancer is a disease that comes from the accumulation of mutations that can begin occurring in their bodies even now. After my presentation, 98.6% of the 305 students who viewed my presentation felt like they had learned something from the presentation and were almost all willing to implement at least one of the changes into their daily lives.
ContributorsGoforth, Michelle Nicole (Author) / Compton, Carolyn (Thesis director) / Lake, Douglas (Committee member) / Popova, Laura (Committee member) / Dean, W.P. Carey School of Business (Contributor) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
A major challenge with tissue samples used for biopsies is the inability to monitor their molecular quality before diagnostic testing. When tissue is resected from a patient, the cells are removed from their blood supply and normal temperature-controlled environment, which causes significant biological stress. As a result, the molecular composition and integrity undergo significant change. Currently, there is no method to track the effects of these artefactual stresses on the sample tissue to determine any deviations from the actual patient physiology. Without a way to track these changes, pathologists have to blindly trust that the tissue samples they are given are of high quality and fit for molecular analysis; physicians use the analysis to make diagnoses and treatment plans based on the assumption that the samples are valid. A possible way to track the quality of the tissue is by measuring volatile organic compounds (VOCs) released from the samples. VOCs are carbon-based chemicals with high vapor pressure at room temperature. There are over 1,800 known VOCs within humans and a number of these exist in every tissue sample. They are individualized and often indicative of a person’s metabolic condition. For this reason, VOCs are often used for diagnostic purposes. Their usefulness in diagnostics, reflectiveness of a person’s metabolic state, and accessibility lends them to being beneficial for tracking degradation. We hypothesize that there is a relationship between the change in concentration of the volatile organic compounds of a sample, and the molecular quality of a sample. This relationship is what would indicate the accuracy of the tissue quality used for a biopsy in relation to the tissue within the body.
ContributorsSharma, Nandini (Co-author) / Fragoso, Claudia (Co-author) / Grenier, Tyler (Co-author) / Hanson, Abigail (Co-author) / Compton, Carolyn (Thesis director) / Tao, Nongjian (Committee member) / Moakley, George (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Cancer is an ever-relevant disease with many genetic, social, environmental, and behavioral risk factors. One factor which has been garnering interest is the impact of nutrition on cancer. As a disease process, cancer is primarily driven by an accumulation of genetic aberrations. Recent epidemiological, pre-clinical, and clinical studies have demonstrated various impacts of bioactive food molecules on the promotion or prevention of these oncogenic mutations. This work explores several of these molecules and their relation to cancer prevention and provides a sample meal plan, which highlights many additional molecules that are currently being studied.
ContributorsCurtin, Elise (Author) / Don, Rachael (Thesis director) / Compton, Carolyn (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2022-05
Description
Cancer is an ever-relevant disease with many genetic, social, environmental, and behavioral risk factors. One factor which has been garnering interest is the impact of nutrition on cancer. As a disease process, cancer is primarily driven by an accumulation of genetic aberrations. Recent epidemiological, pre-clinical, and clinical studies have demonstrated various impacts of bioactive food molecules on the promotion or prevention of these oncogenic mutations. This work explores several of these molecules and their relation to cancer prevention and provides a sample meal plan, which highlights many additional molecules that are currently being studied.
ContributorsCurtin, Elise (Author) / Don, Rachael (Thesis director) / Compton, Carolyn (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2022-05