Browsing by Subject "leukemia"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Combination therapeutics of Nilotinib and radiation in Acute Lymphoblastic Leukemia as an effective method against drug resistance
    (2016-08) Penning, Jackson
    In this work we combine in vitro experimentation with mathematical modeling to study the combined effect of the tyrosine kinase inhibitor nilotinib and ionizing radiation on acute lymphoblastic leukemia cells. We develop a mathematical model for the cell response to this combined therapy. This mathematical model is parameterized via cell viability experiments conducted at a variety of different levels of nilotinib concentration and radiation exposure. We use this parameterized mathematical model to predict cell viability at new levels of nilotinib concentration. These predictions are then compared with new sets of cell viability experiments. We then investigate the structure of optimal radiation dosing schedules under our mathematical model. Finally, the model is expanded to incorporate an additional toxicity constraint on healthy lymphoblast cells, further characterizing optimized treatment protocols.
  • Thumbnail Image
    Item
    Preclinical Dynamic Contrast Enhanced Imaging for Longitudinal Biophysical Assessments of the Healthy and Malignant Vasculature after Radiotherapy
    (2021-06) Brooks, Jamison
    Dynamic contrast enhanced (DCE) imaging acquires time-lapsed images of intravenously injected contrast agents to quantify changes in their delivery to and clearance from the tissue. It is widely used in clinical imaging to assess tissue perfusion and vascular permeability. However, minimal work has been done using DCE in a murine model to better understand the effects of radiotherapy on the vasculature and tissue. This is due in part to a lack of DCE imaging systems with the resolution to directly observe the underlying changes in single-vessel structure and function. In this thesis, I develop and use macroscopic dynamic fluorescent imaging (DynFI) and microscopic quantitative multiphoton microscopy (QMPM). These DCE techniques identify changes in tissue perfusion several days after radiotherapy in the healthy bone marrow, leukemic bone marrow, and solid tumor tissue. DCE imaging can be performed using QMPM while simultaneously observing changes in the single-vessel characteristics for direct correlation. Using QMPM, changes in bone marrow vasculature were observed with the onset of acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Changes included increased angiogenesis, permeability, decreased mean vessel diameter, decreased single-vessel blood flow, and decreased drug delivery. For mice bearing ALL, this resulted in reduced cellular uptake of a chemotherapy surrogate. The results identified potential biomarkers for leukemia using DCE imaging. Treatments ranging from 2 Gy to 10 Gy of total body irradiation (TBI) increased single-vessel blood flow and drug delivery for mice bearing AML and ALL 2 to 5 days after TBI. For mice bearing ALL, targeted 2 and 4 Gy radiotherapy resulted in improved cellular chemotherapy uptake. Additionally, increased survival was observed for mice bearing ALL when administering 4Gy TBI before chemotherapy compared to chemotherapy before 4Gy TBI. Finally, I develop DynFI with principal component analysis to rapidly identify changes in tumor vasculature before and 2 days after 10 Gy targeted radiotherapy. In conclusion, DCE analysis is an effective tool to measure tissue perfusion and vascular function. Increased availability of DCE imaging for preclinical models will allow for a better understanding of the underlying vascular changes that occur in a clinical setting.
  • Thumbnail Image
    Item
    Regulation and Function of the Phosphatase PHLPP2 in Leukemia
    (2017-08) Yan, Yan
    PHLPP2, a member of the PHLPP phosphatase family, which targets oncogenic kinases, has been actively investigated as a tumor suppressor in solid tumors. Little was known, however, regarding its regulation and function in hematological malignancies. The first half of this dissertation describes a novel miR-17~92-based mechanism for repression of PHLPP2 protein expression in late differentiation stage acute myeloid leukemia (AML) subtypes. ATRA (all-trans retinoic acid), a drug used for terminally differentiating AML subtypes, was able to induce PHLPP2 protein levels and phosphatase activity significantly by suppressing miR-17-92 expression. The effect of ATRA on miR-17~92 expression was mediated through its target, transcription factor C/EBP, which interacts with the intronic promoter of the miR-17~92 gene cluster to inhibit its transactivation. The second half of this dissertation provides evidence for a novel metabolic function for PHLPP2 and describes the first identification of the energy sensing kinase, AMPK, as a unique PHLPP2 substrate. PHLPP2 could dephosphorylate phospho-AMPK (T172) both intracellularly and in vitro. PHLPP2 silencing protected Jurkat T-ALL cells from an apoptotic response to low glucose-induced metabolic stress through activation of AMPK signaling. The pro-survival effect of PHLPP2 knockdown under metabolic stress is likely mediated through AMPK-activated fatty acid oxidation. PHLPP2 regulates AMPK phosphorylation in a variety of tumor types and is the first specific AMPK phosphatase to be identified. These studies on PHLPP2 expression and function expand current knowledge and understanding of the role of PHLPP phosphatases in cancer, and particularly in leukemia. In light of the pivotal role played by AMPK in a number of metabolic diseases, the PHLPP2/AMPK axis is also expected to provide new insights into therapies targeting these diseases.