Medicine and Health Sciences Commons^™

Evaluating The Therapeutic Efficacy Of Restoring Wild-Type P53 Activity In P53-Mutant Tumors, Connie A. Larsson

Dissertations & Theses (Open Access)

The p53 transcription factor is the most frequently altered in human cancers usually via missense mutations that undermine its transcriptional activity. Clinically, TP53 mutations have been shown to be remarkably predictive of refractoriness to treatment, resulting in poor outcome. Consequently, the development of p53 pathway activating agents is rapidly evolving and gaining more attention in cancer therapeutics research, with several small molecule compounds currently in preclinical and clinical trials. However, it remains largely unknown what types or proportions of p53-mutant tumors will respond to p53 restoration-based therapies.

Using a mouse model of Li Fraumeni syndrome, we genetically restored wild-type …

Impact Of Kras/Nras Mutational Heterogeneity On Clinical Outcomes In Colorectal Cancer, Jonathan M. Loree

Dissertations & Theses (Open Access)

Introduction: Mutations in KRAS/NRAS (RAS) predict a lack of benefit from anti-EGFR agents in metastatic colorectal cancer (mCRC). As next generation sequencing (NGS) has advanced, we are discovering atypical and low allele frequency mutations. We aimed to evaluate how NGS can optimally define RAS mutant CRC and the role of relative mutant allele frequency (rMAF) as a biomarker.

Methods: Using institutional and public cohorts of mCRC patients with NGS results, we described the prevalence and clinical impact of atypical (not in current guidelines) and low rMAF RAS mutations (RAS MAF by the MAF of the mutated gene with …

Memory Potential, Molecular Characterization, And Translational Applications Of The Novel Theo/Tceo T Cell Phenotype, Todd Bartkowiak, Todd Bartkowiak

Dissertations & Theses (Open Access)

T cells comprise a substantial arm of the immune system and are exquisitely adapted to combat pathogens and tumors. The inflammatory environment largely dictates the nature of T cell response. A hallmark of T cell-mediated immunity is formation of immunological memory; the ability to respond more potently to re-encounter with pathogens. The immune system is also capable of recognizing tumors as foreign, much like viral or bacterial pathogens. Tumors have evolved, though, to generate an immunosuppressive environment to avoid destruction. The field of immunotherapy seeks to overcome immune suppression, in part by targeting T cell co-receptors on the cell surface …

Membrane Bound Il21 Promotes Natural Killer Cell Expansion Through Mir 124-3p Mediated Regulation, Anitha Somanchi

Dissertations & Theses (Open Access)

Natural Killer (NK) cells are cells of the innate immune system that act as first line of defense against viral infections and participate in tumor immune surveillance. NK cells do not cause graft versus host disease (GvHD), or require prior antigen exposure to exert anti-tumor activity, hence are an attractive choice for immunotherapy applications. Owing to small numbers of NK cells in peripheral blood (1-32%, with a 6% median), ex vivo expansion of NK cells is critical for NK cell adoptive immunotherapy, various expansion platforms have been explored over the decades. We developed a robust platform for ex vivo expansion …

Dynamic Assessment Of Nk Cell Interactions With Pediatric Tumor Cells To Predict Response To Immunotherapy, Arianexys Aquino Lopez

Dissertations & Theses (Open Access)

Due to Natural Killer (NK) cells’ capacity to target tumor cells without prior sensitization, adoptive NK cell therapy represents a promising immunotherapy approach for pediatric cancer patients. Our laboratory has developed an NK cell expansion protocol that generates large quantities of NK cells for therapeutic infusion. Given that NK cells are heterogeneous, with variable receptor expression and potential to target tumor cells, the purpose of my study was to determine whether subpopulations of NK cells with enhanced anti-tumor potential could be identified for increased potency of the NK cell infusion product. In addition, we previously showed that our expanded NK …

Project Echo: A Telementoring Program For Cervical Cancer Prevention And Treatment In Low-Resource Settings, Melissa S Lopez, Ellen S Baker, Andrea M Milbourne, Rose M Gowen, Ana M Rodriguez, Cesaltina Lorenzoni, Catherine Mwaba, Susan Citonje Msadabwe, José Humberto Tavares, Georgia Fontes-Cintra, Gustavo Zucca-Matthes, Donato Callegaro-Filho, Danielle Ramos-Martin, Icaro Thiago De Carvalho, Robson Coelho, Renato Moretti Marques, Thiago Chulam, Mila Pontremoli-Salcedo, Fernanda Nozar, Veronica Fiol, Mauricio Maza, Sanjeev Arora, Ernest T Hawk, Kathleen M Schmeler

Journal Articles

Cervical cancer incidence and mortality rates are significantly higher in low- and middle-income countries compared with the United States and other developed countries. This disparity is caused by decreased access to screening, often coupled with low numbers of trained providers offering cancer prevention and treatment services. However, similar disparities are also found in underserved areas of the United States, such as the Texas-Mexico border, where cervical cancer mortality rates are 30% higher than in the rest of Texas. To address these issues, we have adopted the Project ECHO (Extension for Community Healthcare Outcomes) program, a low-cost telementoring model previously proven …

Improvements In Four-Dimensional And Dual Energy Computed Tomography, Rachael M. Martin

Dissertations & Theses (Open Access)

Dual energy and 4D computed tomography (CT) seek to address some of the limitations in traditional CT imaging. Dual energy CT, among other purposes, allows for the quantification and improved visualization of contrast materials, and 4D CT is often used in radiation therapy applications as it allows for the visualization and quantification of object motion. While much research has been done with these technologies, areas remain for potential improvement, both in preclinical and clinical settings, which will be explored in this dissertation. Preclinical dual energy cone-beam CT (CBCT) can benefit from wider separation between the peak energy of the two …

Improving Nk Cell Therapy For Osteosarcoma, Jennifer Foltz

Dissertations & Theses (Open Access)

Osteosarcoma (OS) is the most common primary bone tumor. Despite new treatment options, 5-year survival for metastatic OS has remained at only 30% for the last 30 years. Adoptive transfer of Natural Killer (NK) cells holds promise for a new, non-toxic therapy for OS. NK cells are part of the innate immune system and readily kill metastatic and chemotherapy-resistant OS in vitro and in murine models. However, there is little data regarding their efficacy in animal models with an intact immune system. In addition, the OS tumor microenvironment is highly suppressive, producing TGFβ which impedes NK cell killing of solid …

Hsp27 And Chemotherapy-Induced Autophagy As Biomarkers In Osteosarcoma, John Andrew Livingston

Dissertations & Theses (Open Access)

Survival for patients with osteosarcoma has not improved for > 30 years. Despite aggressive multi-agent chemotherapy combined with surgical resection, a significant fraction of patients with localized disease relapse after optimal treatment. We evaluated the occurrence of cytoplasmic LC3B (light chain 3B)-positive puncta (a marker of autophagy) and presence of HSP27 (heat shock protein 27) in cancer cells within pre-treatment biopsy, post-treatment surgical resection, and metastatic osteosarcoma specimens by immunohistochemistry in 260 patients. LCB3+ puncta expression was seen in 34% of pre-treatment. 50% of resection, and 67% of metastasis samples. Sixty-six percent of all specimens were scored positive for HSP27 (85% …

Managing Variant Discrepancy In Hereditary Cancer: Clinical Practice, Barriers, And Desired Resources, Ellen Zirkelbach

Dissertations & Theses (Open Access)

Variants are changes in the DNA whose phenotypic effects may or may not be definitively understood. Because variant interpretation is a complex process, sources sometimes disagree on the classification of a variant, which is called a variant discrepancy. This study aimed to determine the practice of genetic counselors regarding variant discrepancies and to identify the barriers to counseling a variant discrepancy in hereditary cancer genetic testing. This investigation was unique because it was the first to address variant discrepancies from a clinical point of view. An electronic survey was sent to genetic counselors in the NSGC Cancer Special Interest Group. …

Cyclin B1 Mediates The Effect Of Uchl1 In Promoting Cell Cycle Progression In Uterine Papillary Serous Carcinoma, Suet Ying Kwan

Dissertations & Theses (Open Access)

Uterine papillary serous carcinoma (UPSC) is an aggressive form of endometrial cancer with poor survival rates and a high risk of recurrence. The rarity of UPSC poses challenges to the discovery of novel targeted therapies. Therefore, the purpose of this dissertation was to identify novel therapeutic targets that could aid in the management of UPSC. To do so, we began with the relatively large cohort of UPSC cases in the TCGA data set, which was used to identify differentially expressed genes between UPSC and low-grade endometrioid endometrial carcinoma (EEC) and normal tissue.

We identified Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1 …

Parp Inhibitor Upregulates Pd-L1 Expression And Enhances Cancer-Associated Immunosuppression, Shiping Jiao

Dissertations & Theses (Open Access)

With recent approvals for therapeutic antibodies that block CTLA4, PD-1 and PD-L1, immune checkpoints have emerged as new targets in cancer therapy. In addition, there is accumulating evidence highlighting the role of cancer-associated immunity in patient response to cytotoxic anticancer agents. Inhibitors of poly (ADP-ribose) polymerase (PARP) have shown substantial cytotoxic effects against tumors with defects in DNA damage responses. However, whether a crosstalk between PARP inhibition and immune checkpoints exists remains unclear. Here, it has been shown that PARP inhibitors (PARPis) upregulate PD-L1 expression in multiple cancer cell lines, human xenograft tumors, and syngeneic mouse tumors. Mechanistically, PARPi inactivates …