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Cancer is a heterogeneous disease with discrete oncogenic mechanisms. P53 mutation is the most common oncogenic mutation in many cancers including breast cancer. This dissertation focuses on fundamental genetic alterations enforced by p53 mutation as an indirect target. p53 mutation upregulates the mevalonate pathway genes altering cholesterol biosynthesis and prenylation.

Cancer is a heterogeneous disease with discrete oncogenic mechanisms. P53 mutation is the most common oncogenic mutation in many cancers including breast cancer. This dissertation focuses on fundamental genetic alterations enforced by p53 mutation as an indirect target. p53 mutation upregulates the mevalonate pathway genes altering cholesterol biosynthesis and prenylation. Prenylation, a lipid modification, is required for small GTPases signaling cascades. Project 1 demonstrates that prenylation inhibition can specifically target cells harboring p53 mutation resulting in reduced tumor proliferation and migration. Mutating p53 is associated with Ras and RhoA activation and statin prevents this activity by inhibiting prenylation. Ras-related pathway genes were selected from the transcriptomic analysis for evaluating correlation to statin sensitivity. A gene signature of seventeen genes and TP53 genotype (referred to as MPR signature) is generated to predict response to statins. MPR signature is validated through two datasets of drug screening in cell lines. As advancements in targeted gene modification are rising, the CRISPR-Cas9 technology has emerged as a new cancer therapeutic strategy. One of the important risk factors in gene therapy is the immune recognition of the exogenous therapeutic tool, resulting in obstruction of treatment and possibly serious health consequences. Project 2 describes a method development that can potentially improve the safety and efficacy of gene-targeting proteins. A cohort of 155 healthy individuals was screened for pre-existing B cell and T cell immune response to the S. pyogenes Cas9 protein. We detected antibodies against Cas9 in more than 10% of the healthy population and identified two immunodominant T cell epitopes of this protein. A de-immunized Cas9 that maintains the wild-type functionality was engineered by mutating the identified T cell epitopes. The gene signature and method described here have the potential to improve strategies for genome-driven tumor targeting.
ContributorsRoshdi Ferdosi, Shayesteh (Author) / Anderson, Karen S (Thesis advisor) / LaBaer, Joshua (Thesis advisor) / Woodbury, Neel (Committee member) / Borges, Chad (Committee member) / Arizona State University (Publisher)
Created2017
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Description
Cancer is one of the leading causes of death globally according to the World Health Organization. Although improved treatments and early diagnoses have reduced cancer related mortalities, metastatic disease remains a major clinical challenge. The local tumor microenvironment plays a significant role in cancer metastasis, where tumor cells respond and

Cancer is one of the leading causes of death globally according to the World Health Organization. Although improved treatments and early diagnoses have reduced cancer related mortalities, metastatic disease remains a major clinical challenge. The local tumor microenvironment plays a significant role in cancer metastasis, where tumor cells respond and adapt to a plethora of biochemical and biophysical signals from stromal cells and extracellular matrix (ECM) proteins. Due to these complexities, there is a critical need to understand molecular mechanisms underlying cancer metastasis to facilitate the discovery of more effective therapies. In the past few years, the integration of advanced biomaterials and microengineering approaches has initiated the development of innovative platform technologies for cancer research. These technologies enable the creation of biomimetic in vitro models with physiologically relevant (i.e. in vivo-like) characteristics to conduct studies ranging from fundamental cancer biology to high-throughput drug screening. In this review article, we discuss the biological significance of each step of the metastatic cascade and provide a broad overview on recent progress to recapitulate these stages using advanced biomaterials and microengineered technologies. In each section, we will highlight the advantages and shortcomings of each approach and provide our perspectives on future directions.
ContributorsPeela, Nitish (Author) / Nikkhah, Mehdi (Thesis director) / LaBaer, Joshua (Committee member) / Harrington Bioengineering Program (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
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Description
A coincidence reporter construct, consisting of the p21-promoter and two luciferase genes (Firefly and Renilla), was constructed for the screening of drugs that might inhibit Olig2's tumorigenic role in glioblastoma. The reporter construct was tested using an Olig2 inhibitor, HSP990, as well as short hairpin RNA targeting Olig2. Further confirmatory

A coincidence reporter construct, consisting of the p21-promoter and two luciferase genes (Firefly and Renilla), was constructed for the screening of drugs that might inhibit Olig2's tumorigenic role in glioblastoma. The reporter construct was tested using an Olig2 inhibitor, HSP990, as well as short hairpin RNA targeting Olig2. Further confirmatory analysis is needed before the reporter cell line is ready for high-throughput screening at the NIH and lead compound selection.
ContributorsCusimano, Joseph Michael (Author) / LaBaer, Joshua (Thesis director) / Mangone, Marco (Committee member) / Mehta, Shwetal (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor)
Created2014-05
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Description
Adrenocortical carcinoma (ACC) is a rare and deadly disease that affects 0.5-2 people per million per year in the US. Currently, the first line clinical management includes surgical resection, followed by treatment with the chemotherapeutic agent mitotane. These interventions, however, have limited effectiveness, as the overall five-year survival rate of

Adrenocortical carcinoma (ACC) is a rare and deadly disease that affects 0.5-2 people per million per year in the US. Currently, the first line clinical management includes surgical resection, followed by treatment with the chemotherapeutic agent mitotane. These interventions, however, have limited effectiveness, as the overall five-year survival rate of patients with ACC is less than 35%. Therefore, further scientific investigation underlying the molecular mechanisms and biomarkers of this disease is of high importance. The aim of this project was to identify potential biomarkers that may be used as prognosticators as well as candidate genes that might be targeted to develop new therapies for patients with ACC. An analysis of publicly-available datasets revealed PDZ-binding kinase (PBK) as being upregulated roughly 9-fold in ACC tissue compared to normal adrenal tissue. PBK has been implicated as an oncogene in several other systems, and its expression has been shown to negatively impact patient survival. Initial experiments have confirmed the upregulation of PBK in H295R cells, a human ACC cell line. We effectively silenced PBK (>95% reduction in protein content) in H295R cells using lentiviral shRNA constructs. Using high and low PBK expressing cells, we performed soft agar assays for colony formation, and found that the PBK-silenced cells produced two-fold fewer colonies than the vector control (p<0.05). This indicates that PBK likely plays a role in tumorigenicity. We further conducted functional studies for apoptosis and proliferation to elucidate the mechanism by which PBK increases tumorigenicity. Preliminary results from MTS assays showed that after 9 days, PBK-silenced cells proliferated significantly less than the vector control, so PBK likely increases proliferation. Together these data identify PBK as a kinase implicated in ACC tumorigenesis. Further in vitro and in vivo studies will be conducted to evaluate PBK as a potential therapeutic target in adrenocortical carcinoma.
ContributorsRazzaghi, Raud (Author) / Wilson-Rawls, Jeanne (Thesis director) / Anderson, Karen (Committee member) / Katja, Kiseljak-Vassiliades (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
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Description

Walter Schiller studied the causes of diseases in the US and Austria in the early twentieth century and in 1928, invented the Schiller test, or a way to diagnose early cervical cancer in women. Cervical cancer is the uncontrollable division of cells in the cervix, or lower part of the

Walter Schiller studied the causes of diseases in the US and Austria in the early twentieth century and in 1928, invented the Schiller test, or a way to diagnose early cervical cancer in women. Cervical cancer is the uncontrollable division of cells in the cervix, or lower part of the uterus. While living in Austria until his emigration to escape the Nazis in 1937, Schiller concluded that there was a form of cervical cancer, later named carcinoma in situ, that physicians could detect earlier than when tumors start to appear. To determine whether women exhibited that early form of cancer, Schiller stained women’s cervixes with a type of iodine that would stain healthy cervical tissue and not cancerous cervical tissue. Cervical cancer is more deadly to women when it is caught later in its progression, and was difficult to detect in Schiller's time. Schiller’s research enabled physicians to diagnose cervical cancer early, helping women receive treatment quicker and ultimately helping to popularize annual diagnostic exams in the US.

Created2021-08-12
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Description

In 1913, journalist Samuel Hopkins Adams published “What Can We Do About Cancer? The Most Vital and Insistent Question in the Medical World,” hereafter “What Can We Do About Cancer,” in Ladies’ Home Journal. Cancer is a disease that is the result of abnormal cell division in different parts of

In 1913, journalist Samuel Hopkins Adams published “What Can We Do About Cancer? The Most Vital and Insistent Question in the Medical World,” hereafter “What Can We Do About Cancer,” in Ladies’ Home Journal. Cancer is a disease that is the result of abnormal cell division in different parts of the body, such as the breasts or the cervix. During that time, many women did not discuss or disclose early symptoms of reproductive cancers, such as breast lumps and abnormal vaginal discharge, out of shame or disgust. Thus, people often considered cancer to be a taboo topic. “What Can We Do About Cancer?” provides a representation of what people in the early 1900s thought to be the early warning signs of cancer in women. Although, as of 2021, researchers have made advancements that have increased the scientific understanding of cancer and how it develops, Adams’ article provided women in the US during the 1900s with recommendations on early methods of cancer detection.

Created2021-08-02
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Description

In 2017, Angiolo Gadducci, Silvestro Carinelli, and Giovanni Aletti published, &quot;Neuroendocrine Tumor of the Uterine Cervix: A Therapeutic Challenge for Gynecologic Oncologists,&quot; hereafter, &quot;Neuroendocrine Tumor&quot; in the journal, Gynecologic Oncology. The authors conducted a systematic review of existing literature that documented the symptoms, diagnosis, staging, treatment, and outcomes of women

In 2017, Angiolo Gadducci, Silvestro Carinelli, and Giovanni Aletti published, &quot;Neuroendocrine Tumor of the Uterine Cervix: A Therapeutic Challenge for Gynecologic Oncologists,&quot; hereafter, &quot;Neuroendocrine Tumor&quot; in the journal, Gynecologic Oncology. The authors conducted a systematic review of existing literature that documented the symptoms, diagnosis, staging, treatment, and outcomes of women diagnosed with neuroendocrine tumors, or cervical NETs, which are tumors with cells similar to cells from both the hormonal and the nervous system. Based on high mortality rates and the rarity of cervical NET diagnoses, the authors conclude that cervical NETs present a challenge for physicians in terms of devising novel ideas for treatment. By compiling the treatment methods and resulting outcomes of different studies, the authors presented evidence that there is a need for new forms of treatment to reduce the number of women dying from cervical NETs each year.

Created2022-04-16
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Description

This thesis answers the following question: How does the history of cervical cancer show that prevention helps reduce rates of cancer-related deaths among women? By studying the history of cervical cancer, people can understand how a cancer that was once one of the top killers of women in the US

This thesis answers the following question: How does the history of cervical cancer show that prevention helps reduce rates of cancer-related deaths among women? By studying the history of cervical cancer, people can understand how a cancer that was once one of the top killers of women in the US has declined to become one of the lowest through the establishment of and effective communication of early prevention and diagnostics, both among the general public and within the medical community itself. This thesis is organized based on key episodes which were pertinent to the history of cervical cancer, primarily within the United States and Europe.

Created2021-03-22
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Description

From 1936 to 1945, the Women’s Field Army, hereafter the WFA, educated women in the US on the early symptoms, prevention, and treatment of reproductive cancers. The WFA was a women-led volunteer organization and a branch of, what was then called, the American Society for the Control of Cancer, or

From 1936 to 1945, the Women’s Field Army, hereafter the WFA, educated women in the US on the early symptoms, prevention, and treatment of reproductive cancers. The WFA was a women-led volunteer organization and a branch of, what was then called, the American Society for the Control of Cancer, or ASCC. The WFA, headquartered in New York City, New York, recruited hundreds of thousands of women volunteers across the country. They distributed pamphlets, showed movies, and participated in other grassroots efforts to foster an understanding of reproductive cancers, namely breast and cervical cancer, among other women. The Women’s Field Army aided in reducing the number of cancer-related deaths by spreading cancer prevention awareness and teaching women about their reproductive health and the early detection of cancer, which was one of the first widespread educational resources about reproductive cancers for women.

Created2021-07-31