Theses and Dissertations from UMD
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Item ENGINEERING TARGETED LIGHT ACTIVATABLE NANOPLATFORMS TO MANAGE RECURRENT CANCERS(2024) Pang, Sumiao; Huang, Huang Chiao HH; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cancer recurrence poses a significant challenge in various malignancies that adverselyaffect long-term survival and quality of life. Glioblastoma (GBM) and ovarian cancer exhibit particularly high recurrence rates. For GBM, tumor recurrence is nearly universal (90%) within 10 months post initial treatment due to its invasive characteristics, limited delivery of therapeutic agents, and persistent drug resistance, resulting in a 5-year survival rate of <10%. While standard chemotherapy and surgery can temporarily alleviate symptoms for both diseases, there has been no significant improvement in long-term disease management or survival extension over several decades. Therefore, it is critical to develop targeted therapies that integrates well with current standards of care strategies. Photomedicine is a promising treatment modality, and the two main phototherapies are photodynamic therapy (PDT) which involves photosensitizer administration followed by light activation resulting in non-thermal chemical damage and photothermal therapy (PTT) which involves exogenous or endogenous sensitizing agents followed by light activation resulting in thermal damage. Clinical applications of both modalities have shown its feasibility and safety; however, they face challenges due to (i) limited cancer selectivity, (ii) heterogenous treatment response, and (iii) low monotherapy treatment efficacy. Leveraging strategic therapeutic targets to advance the current sensitizing agents for targeted delivery is a potential solution to overcome these limitations. The overall objective of this dissertation is to advance and evaluate targeted light-activatable nanoplatforms for phototherapy delivery with considerations for the current clinical workflow of GBM and advanced ovarian cancer. This is achieved through the following goals, (1) engineering a novel Fn14 receptor-directed gold nanorods (DART-GNRs) to assess selectivity and PTT efficacy for GBM, and (2) evaluate safety and long-term efficacy of targeted light-activatable multi-agent nanoplatform (tLAMP) to deliver targeted PDT for peritoneal carcinomatosis. First, this work establishes a reproducible synthesis protocol for DART-GNRs, characterizes its photothermal properties, and demonstrate high selectivity towards the Fn14 receptor of cancer cells. Second half of this dissertation established and investigated a two-fiber tissue optical property (TOP) monitoring method for liquid phantoms and for peritoneal carcinomatosis mouse model to enable safer light dosimetry during PDT, established an irinotecan active loading method to reproducibly synthesize tLAMP, and determined tLAMP tumor nodule penetration depth for enhanced targeted PDT combination therapy with adjuvant chemotherapy to enhance long-term survival for ovarian cancer.Item Mathematical Modeling of Cellular Exhaustion to Guide Future Immunotherapy Research(2024) Simmons, Tyler; Levy, Doron; Biophysics (BIPH); Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cellular exhaustion is a dysfunction found in various adaptive immune cells. In chronic settings, like cancer, antigen persistence and prolonged stimulation initiates the development of T cell exhaustion. The exhausted T cell population is a distinct lineage consisting of progenitor exhausted CD8+ T cells and terminally exhausted CD8+ T cells and is characterized by an upregulation of inhibitory receptor frequencies and diminished effector functions. The hypofunctionality of exhausted T cells prevents proper immunity and fails to eradicate the tumor. Recent years have shown a growing interest in targeting T cell exhaustion, attempting to reinvigorate effector functions, as a form of immunotherapy. Though beneficial responses have been reported in clinical settings, patient responses are inconsistent. Complementing the current biological understanding of T cell exhaustion and to advance immunotherapeutic efforts, novel research using mathematical modeling offers valuable insight. Constructing a foundational framework of an exhausted immune response to cancer provides an alternative approach to understanding the tumor-immune system. Presented here is the construction of a mathematical model detailing the development of progenitor and terminally exhausted CD8+ T cell populations in response to a growing tumor. Parameterization and simulation of this model captures biological dynamics observed in experimental and clinical settings. Analysis and conclusions of this model suggest population size and maintenance of progenitor exhausted CD8+ T cells should be a pillar of immunotherapy efforts. Stemming from these conclusions, it was theorized that targeting exhausted CD4+ helper T cells, which, under normal non-chronic conditions, contribute heavily to CD8+ T cell responses, would be a new and effective approach for immunotherapy. To test this hypothesis, the previously constructed model of CD8+ T cell exhaustion was expanded to incorporate CD4+ helper 1 T cells as well as immunosuppressive regulatory T cells. Simulation and analysis of this expanded model further emphasize the need to maintain progenitor exhausted CD8+ T cell numbers. Additionally, model analysis also indicated that the functionality of CD4+ T cells, both regulatory and exhausted CD4+ helper 1 T cells, played a crucial role in tumor persistence. From this work, research regarding CD4+ T cell exhaustion is strongly encouraged. With a better understanding of this dysfunction, CD4+ T cells may be a potentially effective target for future immunotherapy strategies.Item Development of Fluorescent Imaging Methods and Systems to Determine Photodynamic Potential and Inform Cancer Treatment Efficacy(2022) Gaitan, Brandon; Huang, Huang-Chiao; Chen, Yu; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Photodynamic therapy (PDT) is a treatment modality that has gained rapid popularity in both research and clinical settings over the past 20 years. PDT involves harmless red/near-infrared light excitation of non-toxic photosensitizers to generate reactive molecular species (RMS) that can induce tissue damage and/or cell death. In addition, the fluorescence signal generated from the photosensitizer can also be used for optical imaging. These effects have been harnessed for image-guided treatment of cancer and other diseases. As PDT gains popularity, it is crucial to understand and monitor different factors that could impact overall treatment efficacy. These factors include, but are not limited to, the RMS yield of photosensitizers, the distribution of photosensitizers in tissue, and the PDT activation depth in tissues. Our work focused on developing methodologies and devices to characterize and improve PDT treatment. In collaboration with the FDA, we developed a cell-free assay to rapidly and more quantitatively determine the potential phototoxicity of fluorescent probes through the measurement of singlet oxygen. We also developed a method to compare the maximal PDT activation depth of FDA-approved photosensitizers (BPD and PpIX) in the brain. We found that BPD can be activated 50% deeper into brain tissues compared to PpIX at the same radiant exposure. Next, we tested the ability of a 3D imaging system, Fluorescence Laminar Optical Tomography (FLOT), to image the distribution of photosensitizers in the rodent brain. We demonstrated that FLOT could accurately map the photosensitizer distribution up to 0.5 mm in tissues. Lastly, we developed an autofluorescent-based endoscopic imaging system to measure the metabolic impact of PDT on cancer and normal tissues, finding that PDT leads to significant changes in tissue metabolism immediately after treatment. In summary, we have developed a series of systems that can aid in PDT treatment optimization in three major ways:1) rapidly quantifying the singlet oxygen production of photosensitizers, 2) more accurately measuring a photosensitizers localization and activatable depth, and 3) developing the ability to measure a tissues response to PDT in real-time.Item Novel Immunotherapy Agents in Oncology: Generalizability of Trial Results and Drivers of Clinical Utilization(2021) Mishkin, Grace; Franzini, Luisa; Health Services Administration; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cancer is the second most common cause of death in the United States after heart disease. Novel immunotherapy agents such as nivolumab and pembrolizumab have become an essential, albeit extremely expensive, component of oncology care since their first approvals in melanoma in 2014 and lung cancer in 2015. However, little is known about differences between immunotherapy clinical trial participants and the real-world patient population, or about the drivers of provider utilization of these agents. The first objective of this dissertation used the SEER-Medicare linked database with claims data from 2014-2016 to conduct two aims analyzing potential disparities between Medicare beneficiaries on active treatment for melanoma and lung cancer and Medicare clinical trial participants. Aim one compared the characteristics of Medicare patients on active cancer treatment to Medicare patients on active cancer treatment clinical trials. Aim two compared Medicare patients receiving the novel immunotherapy agents nivolumab or pembrolizumab to Medicare patients participating in trials of these two immunotherapy agents. Because of the demographic differences in the melanoma and lung cancer patient populations, these aims were analyzed separately in melanoma and lung cancer. As hypothesized, patients in clinical trials were significantly younger and had fewer comorbid conditions than patients undergoing active cancer treatment not in clinical trials. Underrepresentation of non-White and female patients in clinical trials was hypothesized, but these results were less consistent. The second objective used Medicare Open Payments data from 2016 and Medicare provider utilization data from 2017 to analyze 1) if industry payments promoting nivolumab or pembrolizumab were positively associated with whether a provider was a high utilizer of the agent, and 2) among these high utilizers, if industry payments were positively associated with greater utilization amounts. The hypothesized results, that industry payments were associated with greater likelihood of high utilization and more utilization among high utilizers, were seen in some of the analyses but not consistently throughout the study. Through unique analyses of recent datasets, this dissertation advances our understanding of potential disparities in clinical trial representativeness and the generally positive relationship between promotional payments and provider utilization of immunotherapy agents in the Medicare cancer patient population.Item Mathematical Models of Underlying Dynamics in Acute and Chronic Immunology(2019) Wyatt, Asia Alexandria; Levy, Doron; Applied Mathematics and Scientific Computation; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)During an immune response, it is understood that there are key differences between the cells and cytokines that are present in a primary response versus those present in subsequent responses. Specifically, after a primary response, memory cells are present and drive the clearance of antigen in these later immune responses. When comparing acute infections to chronic infections, there are also differences in the dynamics of the immune system. In this dissertation, we develop three mathematical models to explore these differences in the immune response to acute and chronic infections through the creation, activation, regulation, and long term maintenance of T cells. We mimic this biological behavior through the use of delayed differential equation (DDE) models. The first model explores the dynamics of adaptive immunity in primary and secondary responses to acute infections. It is shown that while we observe similar amounts of antigen stimulation from both immune responses, with the incorporation of memory T cells, we see an increase in both the amount of effector T cells present and the speed of activation of the immune system in the secondary response. We conclude that our model is robust and can be applied to study different types of antigen from viral to bacterial. Extending our work to chronic infections, we develop our second and third models to explore breast cancer dormancy and T cell exhaustion. For our breast cancer dormancy model, we find that our model behaves similar to acute infections, but with constant antigen stimulation. Moreover, we observe the importance of immune protection on the long term survival of breast cancer cells. In our third model we find that while memory T cells play a major role in the effectiveness of the immune system in acute infection, in chronic infections, over long periods of time, T cell exhaustion prevents proper immune function and clearance of antigen. We also observe how the lack of long term maintenance of memory T cells plays an important role in the final outcome of the system. Finally, we propose two potential extensions to the three models developed: creating a simplified acute infection model and creating a combined breast cancer dormancy model with T cell exhaustion.Item PRUSSIAN BLUE NANOIMMUNOTHERAPIES FOR NEUROBLASTOMA(2019) Cano-Mejia, Juliana; Fernandes, Rohan; Fisher, John P; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Neuroblastoma is the most common extracranial solid tumor in children, accounting for 15% of cancer-related deaths. Despite improvements in diagnosis and surgical techniques, neuroblastoma remains challenging to treat due to the heterogeneity of the tumor, low neoantigen expression, immunosuppressive tumor environment, and high recurrence rate. We have therefore engineered a nanoimmunotherapy that combines the advantages of nanotechnology and immunotherapy to combat the aforementioned challenges in treating neuroblastoma. Specifically, our ensemble comprises of Prussian blue nanoparticles (PBNPs) biofunctionalized with the immune adjuvant CpG-oligodeoxynucleotide (CpG). We utilize PBNPs for photothermal therapy (PTT), which ablates tumor cells and releases tumor antigens and adjuvants that increase tumor immunogenicity. Additionally, the PBNPs are biofunctionalized with CpG (CpG-PBNPs) to serve as a depot for local delivery of exogenous immune adjuvants that play an important role in breaking tolerance to tumor antigens and improving tumor antigen presentation. We hypothesize that this approach of targeting tumor cells, antigen presenting cells, and T cells, may hold the key in converting a non-responsive “cold” tumor such as neuroblastoma into a responsive “hot” tumor, leading to better treatments. We first describe the synthesis and characterization of CpG-PBNPs using a facile layer-by-layer coating scheme. The resultant nanoparticles exhibit monodisperse size distributions, multiday stability, and are not cytotoxic. The strong, intrinsic absorption of PBNPs in the CpG-PBNPs is leveraged to administer PTT (CpG-PBNP-PTT) that triggers immunogenic tumor cell death releasing tumor antigens, which increases tumor antigenicity. Simultaneously, the CpG coating functions as an exogenous adjuvant that complements the endogenous adjuvants released by the CpG-PBNP-PTT (e.g. ATP, calreticulin, and HMGB1), increasing adjuvanticity. When administered in a murine model of neuroblastoma, CpG-PBNP-PTT results in complete tumor regression in a significantly higher proportion (70%) of treated animals relative to controls. Further, the long-term surviving, CpG-PBNP-PTT-treated animals reject tumor rechallenge suggesting that our nanoimmunotherapy generates immunological memory. When we treat a synchronous model of neuroblastoma, 50% of nanoimmunotherapy-treated mice show complete eradication of both tumors compared to controls, which showed no survival efficacy. Our findings show the importance of simultaneous cytotoxicity, antigenicity, and adjuvanticity in generating robust and persistent antitumor immune responses. The strategies described in this dissertation encompass novel examples of nanoimmunotherapies to be applied in the clinic for the treatment of neuroblastoma.Item INITIATION AND PROGRESSION OF BRAF/NRAS WILDTYPE MELANOMA IN UV-INDUCED MOUSE MODELS OF CUTANEOUS MELANOMA(2018) Michael, Helen Thompson; Samal, Siba; Merlino, Glenn; Veterinary Medical Science; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Melanoma is the deadliest skin cancer and is responsible for nearly 60,000 deaths worldwide each year. At least some melanomas are believed to arise from stepwise progression from normal melanocytes through a benign nevus stage to malignant melanoma and finally metastatic disease. Approximately 20-50% of melanomas have evidence of a pre-existing nevus, indicating that progression is an important route of melanomagenesis. Ultraviolet radiation exposure is believed to play an important role in nevus and melanoma formation, although the mechanisms of this remain unclear. Childhood sunburn and intermittent sun exposure are epidemiologically linked to increased melanoma risk. While most melanomas have activation of the mitogen activated protein kinase pathway, often due to mutations in BRAF or RAS genes, nearly 15% of cutaneous melanomas do not have an identified strong driver. Despite targeted therapies and immunotherapy, the death rate from melanoma has remained nearly static for several decades, so there is a need to identify additional genes and pathways to provide novel therapeutic targets. We hypothesized that progression of melanocytic lesions from benign to malignant is associated with the acquisition of additional genomic mutations. Unlike wildtype mice, hepatocyte growth factor (HGF) transgenic mice have “humanized” distribution of melanocytes along the dermal-epidermal junction. Following a single dose of UV at 3 days of age, HGF mice develop melanocytic nevi and melanomas. In this project, two HGF models were used to generate melanocytic lesions. The first model, on an albino FVB background had a tumor incidence of only 10% and used melanocyte-specific green fluorescent protein expression to identify early nevi and melanomas. The second model, on a C57BL/6 had a high tumor incidence (80%), and 60% of tumor-bearing mice have metastatic lesions. Sequencing of melanocytic lesions at different stages revealed a variety of driver mutations, including Nf1, Gnaq, and Gna11, as well as genes and pathways with less established roles in melanoma development. Our data provide a broad overview of genes and pathways involved in progression of non-BRAF, non-NRAS melanoma. Additionally, we present the first potential germline variants that may increase metastatic susceptibility for melanoma patients. These genes suggest potential biomarkers for progression of melanocytic lesions.Item SUPPLEMENT USE AMONG A PRE-COLONOSCOPY POPULATION(2018) O'Connor, Shanelle; King-Marshall, Evelyn C; Public and Community Health; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)In the United States, Colorectal Cancer (CRC) is the third leading cause of cancer-related deaths in both males and females. In 2017, it was estimated that 50,260 people would die from colon cancer alone (American Cancer Society, 2017). There are several behavioral factors that are known to reduce the risk of CRC. Studies have shown that less smoking, reduced heavy alcohol use, engaging in regular physical activity and healthy eating habits are associated with a lower risk of developing colorectal cancer (Lynes et al, 2016). In recent studies, researchers found an inverse relationship between Calcium and Vitamin D use and colorectal cancer through various mechanisms (Chan & Giovannucci, 2010). However, the role of other supplements, including multi-vitamins, vitamin C, and vitamin B6, remains uncertain; there have only been a few studies conducted with these other supplements and their role in colon cancer risk reduction. According to Consumer Survey on Dietary Supplements, 68% of U.S. adults report that they use a dietary supplement and over 50% are regular users. NHANES survey shows that women, older adults, and whites use supplements more than their counterparts (Picciano, 2005). A survey was administered to patients prior to their colonoscopy appointment to investigate perceived and actual understanding of the procedure, health literacy, and general health. Participants were selected from eligible patients (18 years or older; could read/write English; cognitively able to fill out survey) scheduled for a colonoscopy at either a university hospital-based center or a university-affiliated outpatient endoscopy center situated in Alachua County, Florida from September 2011 through October 2013 (Curbow et al, 2015). The goal of this proposed Master’s thesis capstone is to conduct a secondary analysis of data collected from patients in this study to determine associations regarding supplement use with various variables such as demographic factors, perceived health literacy, informed about CRC, concern about CRC, reason for colonoscopy and general health. These associations will help us to better understand how these variables impact supplement use among this population.Item Mathematical Models for Ovarian Cancer(2017) Botesteanu, Dana-Adriana; Levy, Doron; Applied Mathematics and Scientific Computation; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Ovarian cancer is the most fatal cancer of the female reproductive system. High-grade serous ovarian cancer (HGSOC) represent the majority of ovarian cancers and accounts for the largest proportion of deaths from the disease. From a clinical perspective, the complex, heterogeneous behaviors of this women's cancer pose questions that cannot always be answered with contemporary clinical and experimental tools. Studying the growth, progression, and dynamic response to treatment of ovarian cancers in an integrated systems biology/mathematical framework offers an innovative tool at the disposal of the oncological community to further exploit readily available clinical data and generate novel testable hypotheses. Developing novel physiologically structured mathematical models to study the heterogeneous behavior of this malignancy would help us to better understand patient therapeutic responses and devise novel combination therapies. As a first step, we developed a mathematical model for a quantitative explanation why transvaginal ultrasound-based (TVU) screening fails to improve low-volume detectability and overall survival (OS) of HGSOC. This mathematical model can accurately estimate the efficacy of screening for this cancer subtype. The model also explains the observed heterogeneity in cancer progression and duration of the pre-diagnosis stage. Our mathematical model is consistent with recent case reports and prospective TVU screening population studies, and provides support to the empirical recommendation against frequent HGSOC screening. At the cell population level, we have quantitatively investigated the role of cell heterogeneity emerging from variations in cell-cycle parameters and cell-death. Many commonly used chemotherapeutic agents in treating ovarian cancers target only dividing cancer cells. We recently demonstrated in a mathematical model, calibrated against published in vitro cell culture data, that resistance to chemotherapeutic treatment may arise from a dynamic, oscillatory balance between the dividing and non-dividing cancer cells, which is conserved through time despite high long-term drug dosages. At the single cell level, we developed a mathematical model to explain the emerging heterogeneity in individual cancer cell responses to drugs targeting the cell-cycle, which have a broad spectrum of anti-tumor activity in ovarian cancers. This emerging heterogeneity remains a poorly understood mechanism that plays a significant role in mediating drug response, and predicts the existence of an intrinsic resistance mechanism to drug therapy. The model incorporates an intrinsic form of heterogeneity via the duration of time single cells spend in mitosis. It uses published single cell in vitro experimental data for calibration. Herein, the goal is to better understand why, within a distinct cell line, cells treated with identical drugs exhibit a considerable degree of heterogeneity in response to prolonged drug exposure. The model can serve as a basis for future studies of the heterogeneity observed in vitro of more complex responses to anti-mitotic drugs of different cell lines. Studying the natural history, growth, and progression of ovarian cancers in an integrated systems biology/mathematical framework represents a complementary tool that can be used to provide valuable insights into the treatment of HGSOC. My work focuses on developing and applying quantitative, integrated mathematical modeling frameworks to pre-clinical and clinical data, in order to better understand ovarian cancer dynamics and develop new therapeutics.Item EXPLORING IL-7R-ALPHA DEVELOPMENTAL EFFECTS AND ONCOGENIC COLLABORATIONS(2017) Cramer, Sarah Delia; Samal, Siba; Veterinary Medical Science; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Acute lymphoblastic leukemia is the most common cancer of children. Individual cases of leukemia may have multiple genetic lesions, and identifying those that drive leukemogenesis will be important in the development of targeted therapy. Approximately 10% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) cases have a mutation in IL-7Rα. These mutations are thought to be oncogenic, but little is known about the effects of the mutation on T-cell development. In addition, the mutation does not seem to induce leukemia in the absence of other genetic lesions, suggesting that collaborative mutations are required for leukemogenesis. Based on patient data, potential collaborators include TLX3 expression, HOXA gene cluster overexpression, and NRAS mutation. Given the current state of knowledge regarding mutant IL-7Rα, this project was developed with two specific aims. The first was to investigate the effects of mutant IL-7Rα gain-of-function (IL-7Rα-GOF) on T-cell development in vitro and in vivo. The second was to determine whether candidate collaborative genetic lesions would drive T-ALL formation when combined with mutated IL-7Rα. To address these aims, immature murine thymocytes were cultured on an OP9-DL4 stromal cell system, transduced with retroviral vectors, and injected into sub-lethally irradiated Rag1-/- mice. Resultant diseases were analyzed using a variety of techniques including flow cytometry, histology, immunohistochemistry, ligation-mediated PCR, TCRβ clonality assessment, RNA-sequencing, serial passage, and limiting dilution assay. Studies showed that IL-7Rα-GOF mutation caused an increase of CD8+ cells in vitro. When thymocytes transduced with IL-7Rα-GOF mutation were injected into mice, animals developed a multi-systemic inflammatory disease. This inflammation was not due to imbalance in populations of Treg and Th17 cells, as had been hypothesized. Assessing collaborations with TLX3 expression, HOXA overexpression, and NRAS mutation showed that combination of these genetic lesions with IL-7Rα-GOF mutation caused different neoplastic diseases. The combination of IL-7Rα-GOF mutation and TLX3 expression caused low-penetrance, late-onset T-cell lymphoma. Thymocytes overexpressing the HOXA gene cluster and transduced with IL-7Rα-GOF mutation caused a rapid-onset myeloid leukemia. Combination of IL-7Rα-GOF mutation with mutant NRAS yielded rapid-onset, full-penetrance T-cell lymphoblastic leukemia, suggesting that this combination of mutations was sufficient to induce T-ALL. These experimental results may help to lay the foundation for the development of targeted therapy for pediatric T-ALL.