Browsing by Subject "Cancer biology"

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    Delineating the APOBEC3 enzymes responsible for the APOBEC mutation signature in cancer
    (2021-08) Jarvis, Matthew
    Mutations drive the initiation and progression of cancer. The leading druggable source of mutation in cancer, cytosine deamination by a subset of the nine-membered APOBEC family of DNA deaminase enzymes, leaves a distinct mutation signature on the cancer genome. This signature is characterized as C-to-T and C-to-G mutations in a TCA/T trinucleotide context, and thus APOBEC-dependent mutations can be resolved computationally from other processes of mutation in clinical next-generation tumor sequencing datasets. While specific APOBEC3 (A3) enzymes have been implicated as the main progenitors of this mutation signature (namely, APOBEC3A, APOBEC3B, and APOBEC3H, abbreviated A3A, A3B, and A3H), the literature is full of conflicting data and it is not clear which of these enzymes contributes most prominently, and whether other A3 enzymes may also contribute to mutation in cancer. In this thesis, we aim to definitively characterize the A3 enzymes that can contribute to genomic mutation in a mammalian cell, and potentially be involved in cancer mutagenesis. To accomplish this, we utilized bioinformatic approaches to understand mutational profiles in >1000 cancer cell models, the capacity of individual A3s to generate a cellular damage response and genomic mutation in culture, and the carcinogenic action of APOBECs in multiple animal systems of cancer initiation and progression. Taken together, these analyses indicate that both A3A and A3B have the capacity to generate a mutation signature in mammalian cells, and that A3A has the ability to initiate tumor formation in vivo. These novel advancements in the APOBEC biology field could prove invaluable in the design and implementation of future therapies and diagnostics targeting the A3s in cancer. An understanding of enzyme-specific mutational capacity will improve the development of targeted therapies, which could span to small molecule inhibition of enzymatic activity, synthetic lethal strategies, or immunotherapy-based approaches to selectively kill A3-expressing tumor cells, with the ultimate goal of attenuating or exploiting this mutational process to improve poor clinical outcomes (including drug resistance and metastasis).
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    Mechanisms of Action for Ad5-TRAIL/CpG Immunotherapy for the Treatment of Renal Cell Carcinoma
    (2014-06) James, Britnie Ryan
    Renal cell carcinoma (RCC) affects ~65,000 people in the U.S. annually. About 30% of RCC patients have multiple metastases at diagnosis, and an equal percentage will develop metastatic tumor recurrence after nephrectomy. Metastatic RCC is incurable, with a median survival time of only 18 months. Immune-based therapy for RCC provides the potential for long-lived protection against reoccurrence. However, even the most successful immunotherapy-based clinical trials only show objective response rates in <50% of the patients. Many factors may account for this limited clinical success, including pre-clinical use of young, normal weight ("lean") animals lacking immunomodulatory co-morbidities present in many cancer patients. Obesity is one of the main risk factors and co-morbidities for RCC. The reasons for this are likely complex and multifactorial, but generalized immune suppression during obesity may contribute to these findings. Due to the negative effects of obesity on the immune system, studies are needed to provide a framework from which novel immunotherapies can be developed for patients with metastatic RCC that is complicated by such co-morbidities. In a subcutaneous RCC model we have demonstrated that Ad5-TRAIL/CpG immunotherapy could eradicate local tumors. However, the mechanisms by which this therapy worked in a metastatic model and the negative effects obesity may exert were not known. Using a model of metastatic RCC we found that lean mice required CD8αDC and pDC to mount an antitumor CD8+ T cell response capable of clearing tumors, following Ad5-TRAIL/CpG treatment. Mice complicated with diet-induced obesity (DIO) presented with immune dysregulations in both the DC and CD8+ T cell compartments. Additionally, Ad5-TRAIL/CpG therapy modulated the immunosuppressive MDSC population in lean mice, but not in DIO mice. These data correlated with the inability of DIO mice to respond to Ad5-TRAIL/CpG therapy and they ultimately succumbed to tumor burden. The research presented here highlights the immunosuppression evident in the obese environment and demonstrate the importance of examining co-morbidities, such as obesity, in pre-clinical studies for novel therapies.