Matching Items (8)
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- All Subjects: Cancer
- Creators: Compton, Carolyn
- Member of: Theses and Dissertations
Description
The purpose of this project is to explore the benefit of using prodrugs in chemotherapy, as well as to explain the concept of angiogenesis and the importance of this process to tumor development. Angiogenesis is the formation of new blood capillaries that are necessary for the survival of a tumor, as a tumor cannot grow larger than 1-2 mm3 without developing its own blood supply. Vascular disrupting agents, such as iodocombstatin, a derivative of combretastatin, can be used to effectively cut off the blood supply to a growing neoplasm, effectively inhibiting the supply of oxygen and nutrients needed for cell division Thus, VDAs have a very important implication in terms of the future of chemotherapy. A prodrug, defined as an agent that is inactive in the body until metabolized to yield the drug itself, was synthesized by combining iodocombstatin with a β-glucuronide linker. The prodrug is theoretically hydrolyzed in the body to afford the active drug by β-glucuronidase, an enzyme that is produced five times as much by cancer cells as by normal cells. This effectively creates a “magic-bullet” form of chemotherapy, known as Direct Enzyme Prodrug Therapy (DEPT).
ContributorsClark, Caroline Marie (Author) / Pettit, George Robert (Thesis director) / Melody, Noeleen (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor)
Created2015-05
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
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
Evolutionary theory provides a rich framework for understanding cancer dynamics across scales of biological organization. The field of cancer evolution has largely been divided into two domains, comparative oncology - the study of cancer across the tree of life, and tumor evolution. This work provides a theoretical framework to unify these subfields with the intent that an understanding of the evolutionary dynamics driving cancer risk at one scale can inform the understanding of the dynamics on another scale. The evolution of multicellular life and the unique vulnerabilities in the cellular mechanisms that underpin it explain the ubiquity of cancer prevalence across the tree of life. The breakdown in cellular cooperation and communication that were required for multicellular life define the hallmarks of cancer. As divergent life histories drove speciation events, it similarly drove divergences in fundamental cancer risk across species. An understanding of the impact that species’ life history theory has on the underlying network of multicellular cooperation and somatic evolution allows for robust predictions on cross-species cancer risk. A large-scale veterinary cancer database is utilized to validate many of the predictions on cancer risk made from life history evolution. Changing scales to the cellular level, it lays predictions on the fate of somatic mutations and the fitness benefits they confer to neoplastic cells compared to their healthy counterparts. The cancer hallmarks, far more than just a way to unify the many seemingly unique pathologies defined as cancer, is a powerful toolset to understand how specific mutations may change the fitness of somatic cells throughout carcinogenesis and tumor progression. Alongside highlighting the significant advances in evolutionary approaches to cancer across scales, this work provides a lucid confirmation that an understanding of both scales provides the most complete portrait of evolutionary cancer dynamics.
ContributorsCompton, Zachary Taylor (Author) / Maley, Carlo C. (Thesis advisor) / Aktipis, Athena (Committee member) / Buetow, Kenneth (Committee member) / Nedelcu, Aurora (Committee member) / Compton, Carolyn (Committee member) / Arizona State University (Publisher)
Created2023