Chemicals and Drugs Commons^™

Expanding Inducible Epithelial Resistance Against Pneumonia: Novel Virus, Novel Receptor, Michael Longmire

Dissertations and Theses (Open Access)

Pneumonia is the leading infectious cause of death worldwide and presents a continuing risk among immunocompromised patients. Our work has been focused for many years on the phenomenon of inducible epithelial resistance, where activation of the innate immune response in the airway epithelium is necessary and sufficient to produce a pathogen-killing but self-protective environment to prevent severe disease. Inducible resistance is pathogen-agnostic and has been demonstrated against an array of respiratory infections. We achieve this using a combination of pattern recognition receptor agonists – Pam2CSK4 and ODN M362 being the current formulation – which produce synergistic levels of pathogen reduction …

The Role Of Ucp2 In Pancreatic Cancer Metabolism And Its Potential As A Radiosensitizer, Emily Rieff

Dissertations and Theses (Open Access)

Uncoupling protein 2 (UCP2) is a mitochondrial protein that regulates the flow of protons down the gradient established by the electron transport chain (ETC) without generating ATP, thus uncoupling the proton gradient from ATP generation. In tumors, specifically pancreatic cancer (PDAC), the ETC is highly stimulated to generate the copious ATP needed by the tumor to grow. However, extended ETC use increases reactive oxygen species (ROS), and if left unchecked, results in cell death. To evade this, PDAC employs antioxidant strategies, including upregulating UCP2 in tumor cells. In addition to its uncoupling function, UCP2 indirectly controls ROS levels by maintaining …

Impact Of Tumor Cell Expressed Cd38 On Metastasis And Immune Evasion In Breast Cancer, Tanvi Visal

Dissertations and Theses (Open Access)

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype. The epithelial-to-mesenchymal transition (EMT) of cancer cells is a key feature of the metastatic cascade and is not a binary process but often generates malignant cells with both epithelial (E) and mesenchymal (M) traits known as hybrid EM cells. Recent studies highlight the enhanced metastatic potential of the hybrid EM cells. However, molecular insights and targetable vulnerabilities within hybrid EM remain elusive. We discovered that hybrid EM murine tumors are enriched in CD38, an immunesuppressive molecule associated with worse clinical outcomes in liquid malignancies but relatively understudied in solid …

Investigating Prefrontal Cortex Neuronal Signatures Of Opioid-Induced Risk-Taking Behavior, Cana Quave

Dissertations and Theses (Open Access)

Opioid use disorder occurs alongside impaired risk-related decision-making, but the underlying neural correlates are unclear. We developed an approach-avoidance conflict task using a modified conditioned place preference procedure to study neural signals of risky opioid seeking in the prefrontal cortex, a region implicated in executive decision-making. Following morphine conditioned place preference, rats underwent a conflict test in which fear-inducing cat odor was introduced in the previously drug-paired side of the apparatus. While the saline-exposed control group avoided cat odor, the morphine group included two subsets of rats that either maintained a preference for the paired side despite the presence of …

Investigating The Role Of Insulin-Like Signaling In Paclitaxel-Induced Nociceptive Hypersensitivity Using Drosophila Melanogaster, Sreepradha Sridharan

Dissertations and Theses (Open Access)

Paclitaxel (PTX), a chemotherapeutic that alters microtubule dynamics, is known to induce nociceptive hypersensitivity and sensory neuron damage in human patients and in Drosophila larvae. We used a modified feeding protocol to establish a genetically tractable Drosophila model of PTX-induced hypersensitivity. Larvae fed PTX exhibited hypersensitivity to thermal and mechanical stimuli. Thermal hypersensitivity was observed at low concentrations of PTX (even below 1 μM per ml of food), begins within 8 hours of PTX feeding, and did not completely resolve at the larval stage. Live imaging of peripheral thermal nociceptors showed that this hypersensitivity precedes observable neuronal damage. At low …

Evaluation Of Myogenic Differentiation Potential Of Bmd Ipscs In Vitro And The Effect Of Ubiquitination Inhibitors On Dystrophin Stability In Vivo, Muchen Liu

Dissertations and Theses (Open Access)

Background: Muscular dystrophies are heterogeneous groups of inherited diseases leading to progressive muscular weakness and degeneration. In the case of Becker muscular dystrophy (BMD), non-disrupting mutations of the DMD gene reading frame is the causative defect. By the age of 30s, about 60 to 70% of BMD patients develop cardiomyopathy, which is often lethal. Unfortunately, there is currently no cure for BMD. Meanwhile, improvement of dystrophin stability by repressing polyubiquitination is a promising strategy. The application of human iPSCs in tissue regeneration also serves as a potential therapeutic strategy. This study aims to test the efficacy of selected drugs interfering …

Epiregulin As A Novel Target For Antibody-Drug Conjugate Development For The Treatment Of Colorectal Cancer, Joan Jacob

Dissertations and Theses (Open Access)

Antibody-drug conjugates (ADCs) are a fast-growing class of molecularly targeted therapies with 13 currently approved and over a 100 in clinical trials. ADCs consist of a monoclonal antibody (mAb) conjugated to a potent cytotoxic payload to selectively target tumor antigens highly expressed on the cell surface. ADC development has been limited in colorectal cancer (CRC) by the lack of novel and effective therapeutic targets. Epiregulin (EREG), is an epidermal growth factor receptor (EGFR) ligand that is highly expressed in CRCs of different subtypes and mutational statuses with low expression in normal tissues. Here, we have characterized the role of EREG …

Uncovering Molecular Targets To Overcome Immunosuppression In Non-Small Cell Lung Cancer With Acquired Tki Resistance, Sonia A. Patel

Dissertations and Theses (Open Access)

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Targeted therapeutic agents, such as epidermal-like growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) or monoclonal antibodies targeting vascular endothelial growth factor (VEGF/R), can effectively inhibit upregulated signaling pathways driving tumorigenesis in NSCLC and many other cancers. Unfortunately, however, resistance to such targeted therapies inevitably arise in most patients and can occur through a variety of resistance mechanisms including genomic alterations and upregulation of bypass pathways. Additionally, patients who have acquired resistance to these targeted agents typically have tumors characterized by an immunosuppressive tumor microenvironment and thus …

The Impact Of Treatment With Palynziq® On Quality Of Life For Individuals With Pku, Teresa Heller

Dissertations and Theses (Open Access)

Management for phenylketonuria (PKU) has traditionally involved adhering to a strict low-protein diet to maintain phenylalanine (Phe) levels within the recommended range (μmol/L). The time commitment and financial, emotional, and social burdens of adhering to a restrictive diet, as well as the neurocognitive symptoms associated with elevated Phe levels, make it challenging to manage PKU and lead to reductions in quality of life. Palynziq^® is an enzyme substitution therapy used to lower blood Phe levels and liberate individuals with PKU from their restrictive diets. Previous studies have demonstrated the safety and efficacy of Palynziq^®, but our study …

Hdac6 Inhibition Reverses Long-Term Doxorubicin-Induced Cognitive Dysfunction By Restoring Microglia Homeostasis, Blake Mcalpin

Dissertations and Theses (Open Access)

One in 8 women in the US will be diagnosed with breast cancer. Currently, doxorubicin is one of the most effective chemotherapies for breast cancer. Unfortunately, up to 60% of survivors report long-term chemotherapy-induced cognitive dysfunction (CICD) characterized by deficits in working memory, processing speed, and executive functioning. Currently, no interventions for CICD have been approved by the US Food and Drug Administration. I show here that a 14-day treatment with a blood-brain barrier permeable histone deacetylase 6 (HDAC6) inhibitor successfully reverses long-term CICD following a therapeutic doxorubicin dosing schedule in female mice, as assessed by the puzzle box test …

Targeting Plasma Membrane Phosphatidylserine Content To Inhibit Oncogenic Kras Function, Walaa E. Kattan

Dissertations and Theses (Open Access)

The small GTPase KRAS, which is frequently mutated in human cancers, must be localized to the plasma membrane (PM) for biological activity. We recently showed that the KRAS C-terminal membrane anchor exhibits exquisite lipid-binding specificity for select species of phosphatidylserine (PtdSer). We therefore investigated whether reducing PM PtdSer content is sufficient to abrogate KRAS oncogenesis. Oxysterol-related binding proteins ORP5 and ORP8 exchange PtdSer synthesized in the ER for phosphatidylinositol-4-phosphate (PI4P) synthesized in the PM. We show that depletion of ORP5 or ORP8 reduced PM PtdSer levels, resulting in extensive mislocalization of KRAS from the PM. Concordantly, ORP5 or ORP8 depletion …

Nuclear-Targeted Gold Nanoparticles Enhance The Effects Of Radiation Therapy With And Without Liposomal Delivery, Maureen Aliru

Dissertations and Theses (Open Access)

Less that 10% of pancreatic cancer patients are eligible for curative resection, and clinical trials evaluating chemoradiation in locally advanced patients with unresectable disease have been largely disappointing. New and creative therapeutic approaches are needed to address the unment need for treatment options. The objective of this thesis is to advance radiosensitization of treatment-resistant densely desmoplastic pancreatic cancer using nanoparticles to surmount biological barriers to effective particle distribution for DNA-targeting.

Clinical translation of radiosensitizing nanoparticles has stalled owing to technical challenges. Current strategies to use AuNPs for radiosensitization require large quantities of gold, kilovoltage x-rays, immediate irradiation after intravenous administration, …

Great Expectations: Phosph(On)Ate Prodrugs In Drug Design—Opportunities And Limitations, Victoria Yan

Dissertations and Theses (Open Access)

Phosphate and phosphonates are chemical moieties with historical precedence in anticancer and antiviral nucleotide analogues. Synchronous to modern efforts identifying novel therapeutic targets in cancer, such chemical moieties are being investigated in the design of novel inhibitors with antineoplastic potential. A central challenge to the delivery of phosph(on)ate-containing drugs is their anionic character at physiological pH, which portends poor membrane permeability. This limitation has been successfully overcome through the use of prodrugs. When attached to the phosph(on)ate moiety, prodrugs mask the negative charge and easily enable cell permeability. Upon cellular entry, the promoieties are enzymatically or environmentally cleaved to unveil …

Directed Evolution Of Macrocyclic Peptides For Inhibition Of Autophagy, Joshua Gray

Dissertations and Theses (Open Access)

In recent decades it has become increasingly clear that induction of autophagy plays an important role in the development of treatment resistance and dormancy in many cancer types. Chloroquine (CQ) and hydroxychloroquine (HCQ), two autophagy inhibitors in clinical trials, suffer from poor pharmacokinetics and high toxicity at therapeutic dosages. This has prompted intense interest in the development of targeted autophagy inhibitors to re-sensitize disease to treatment with minimal impact on normal tissue. We utilized Scanning Unnatural Protease Resistant (SUPR) mRNA display to develop macrocyclic peptides targeting the autophagy protein LC3. The resulting peptides bound LC3A and LC3B—two essential components of …

Impact Of Epa And Dha Supplementation And 15-Lox-1 Expression On Colitis And Colitis-Associated Colorectal Cancer, Jonathan Jaoude

Dissertations and Theses (Open Access)

Inflammatory bowel disease (IBD) patients not only suffer from colitis but also from increased morbidity and mortality of colitis-associated colorectal cancer (CAC). The enzyme 15-lipoxygenase-1 (15-LOX-1) is crucial to converting omega-3 fatty acid derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to resolvins, potent anti-inflammatory products. 15-LOX-1 effects on the conversion of EPA and DHA to resolvins that subsequently exert anti-inflammatory and anti-tumorigenic effects have received little attention. To address this knowledge gap, we hypothesize that 15-LOX-1 expression in colonic epithelial cells is essential for resolvin biosynthesis from EPA and DHA to modulate immunophenotype, limit inflammation, promote resolution, and help …

Evaluating The Therapeutic Efficacy Of Grb2 Inhibition In Ovarian Malignancies, Olivia Lara

Dissertations and Theses (Open Access)

Purpose: Adaptor proteins such as growth factor receptor-bound protein-2 (Grb2) play important roles in cancer cell signaling. In the present study, we examined the biological effects of liposomal antisense oligodeoxynucleotide that blocks Grb2 expression (L-Grb2) in ovarian cancer models.

Experimental Design: Murine orthotopic models of ovarian cancer (OVCAR5 and SKOV3ip1) were used to study the biological effects of L-Grb2 on tumor growth. In vitro experiments (cell viability assay, Western blot analysis, siRNA transfection, and reverse phase protein array) were carried out to elucidate the mechanism and potential predictors of tumor response to L-Grb2.

Results: Treatment with L-Grb2 decreased tumor growth …

The Regulation Of Dna Methylation In Mammalian Development And Cancer, Nicolas Veland

Dissertations and Theses (Open Access)

DNA methylation is an essential epigenetic modification in mammals, as it plays important regulatory roles in multiple biological processes, such as gene transcription, maintenance of chromosomal structure and genomic stability, genomic imprinting, retrotransposon silencing, and X-chromosome inactivation. Dysregulation of DNA methylation is associated with various human diseases. For example, cancer cells usually show global hypomethylation and regional hypermenthylation, which have been implicated in genomic instability and tumor suppressor silencing, respectively. Although great progress has been made in elucidating the biological functions of DNA methylation over the last several decades, how DNA methylation patterns and levels are regulated and dysregulated is …

Gcn5 Impacts Fgf Signaling At Multiple Levels And Activates C-Myc Target Genes During Early Differentiation Of Embryoid Bodies, Li Wang

Dissertations and Theses (Open Access)

Precise control of gene expression during development is orchestrated by transcription factors, signaling pathways and co-regulators, with complex cross-regulatory events often occurring. Growing evidence has identified chromatin modifiers as important regulators for development as well, yet how particular chromatin modifying enzymes affect specific developmental processes remains largely unclear. Embryonic stem cells (ESCs) are self-renewing, pluripotent, and have the abilities to generate almost all cell types in adult tissues. The dual capacity of ESCs to self-renew and differentiate offers unlimited potential for studying gene regulation events at specific developmental stages in vitro that parallel developmental events during embryogenesis in vivo. …

Characterization And Reversal Of Doxorubicin-Mediated Changes In Sensory Neurons, Brittany L. Coughlin

Dissertations and Theses (Open Access)

Chemotherapeutic agents impair memory in humans as well as in animal models. Such memory impairments can be persistent, lasting years after exposure to chemotherapy. Doxorubicin (DOX), a common chemotherapeutic agent, has been associated with memory impairments in humans and induces memory deficits in rodent models. DOX also impairs serotonin (5-HT)-induced long-term synaptic facilitation (LTF) in Aplysia sensorimotor co-cultures, a cellular analog of long-term memory formation. In addition, DOX leads to dynamic activation of extracellular signal-regulated kinase (ERK), consisting of an immediate and a delayed phase of activation, and to transient activation of p38 mitogen-activated protein kinase (p38 MAPK) in Aplysia …

Circumventing Cisplatin Resistance In Ovarian Cancers Through Reactivation Of P53 By Non-Cross-Resistant Platinum Analogs, Michelle Martinez-Rivera

Dissertations and Theses (Open Access)

Abstract

CIRCUMVENTING CISPLATIN RESISTANCE IN OVARIAN CANCERS THROUGH REACTIVATION OF P53 BY NON-CROSS-RESISTANT PLATINUM ANALOGS

Michelle Martinez-Rivera, B.S.

Advisory Professor: Zahid H. Siddik, Ph.D.

Cisplatin (cis-Pt), an anticancer platinum (Pt) drug, is used widely in the treatment of several malignancies, such as ovarian cancer. This Pt compound induces DNA damage, which results in p53 activation through post-translational modifications, mainly phosphorylation, culminating in execution of programmed cell-death. However, despite initial therapeutic response to cis-Pt, clinical resistance to this drug emerges leading to disease progression. Pt-resistance phenotypes have been associated with dysfunction in the p53 signaling pathway. Therefore, an effort to understand …

An Automated Syringe Pump System For Improving The Reproducibility Of Dynamic Hyperpolarized Mri Phantoms, Harlee G. Harrison

Dissertations and Theses (Open Access)

AN AUTOMATED SYRINGE PUMP SYSTEM FOR IMPROVING THE REPRODUCIBILITY OF DYNAMIC HYPERPOLARIZED MRI PHANTOMS

Harlee Grace Harrison, B.S.

Advisory Professor: James Bankson, Ph.D.

Magnetic Resonance Imaging (MRI) is a powerful tool in the diagnosis of cancer due to its ability to provide good soft tissue contrast and image resolution without the use of ionizing radiation. The use of hyperpolarized pyruvate as a contrast agent for tumor metabolism during MR scans has the potential to provide information about tumor metabolism in vivo that is not available from traditional imaging measurements or any other method. Hyperpolarization is achieved through dynamic nuclear polarization. …

Targeting Oncogenic Mirnas With Small Molecules For Breast Cancer Therapy, Paloma Del C. Monroig

Dissertations and Theses (Open Access)

The crucial role of microRNAs (miRNAs) in cancer pathobiology has driven the introduction of new drug development approaches such as miRNA inhibition. In order to advance miRNA-therapeutics, there is a need to develop screening strategies that can target tumors in a specific way. Small molecule inhibitors represent an attractive approach to pursue this. However, the absence of molecular structures for most of the miRNAs makes it very difficult to predict which inhibitors can bind to them. Herein we designed a strategy to screen for small molecules by assesing whether they could directly bind/ interact with miR-10b/miR-21. As part of our …

Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd

Dissertations and Theses (Open Access)

Normal Glycolytic Enzyme Activity is Critical for Hypoxia Inducible Factor-1α Activity and Provides Novel Targets for Inhibiting Tumor Growth

By Geoffrey Grandjean

Advisory Professor: Garth Powis, D. Phil

Unique to proliferating cancer cells is the observation that their increased need for energy is provided by a high rate of glycolysis followed by lactic acid fermentation in a process known as the Warburg Effect, a process many times less efficient than oxidative phosphorylation employed by normal cells to satisfy a similar energy demand ^[1]. This high rate of glycolysis occurs regardless of the concentration of oxygen in the cell and …

Src Homology 2 Domain-Containing 5’-Inositol Phosphatase-2 (Ship2) Is An Effector Of Lymphatic Dysfunction, Germaine D. Agollah

Dissertations and Theses (Open Access)

The lymphatic system is essential for the transport of excess fluid, protein, and foreign materials from interstitial tissues to lymph nodes; for immune surveillance, and to maintain fluid homeostasis. Dysregulated lymphatics can be attributed to pathological conditions including tumor metastasis, inflammation, chronic wounds, obesity, blood vascular disorders, and lymphedema. Of these, lymphedema is the most extreme of lymphatic disorders and is represented by a spectrum of symptoms ranging from mild, subtle presentation to severe, disfiguring, overt presentation. Lymphedema is more manageable in the early stages of disease but severely reduces quality of life with progression. Due to lack of molecular …

Mapping The Human Vasculature By In Vivo Phage Display, Julianna Bronk

Dissertations and Theses (Open Access)

In vivo phage display screenings by intravenous injection of a random phage-displayed peptide library allow for the selection of peptides that localize to specific vascular beds. At the University of Texas MD Anderson Cancer Center, we have had the opportunity to perform phage display screenings in cancer patients in order to select for cancer specific targets directly in humans. These targets serve to define biochemical diversity of endothelial cell surfaces and can be validated and explored towards the design of vascular-targeted pharmacology. In the most recent patient screen, samples were recovered from hepatocellular carcinoma (HCC) as well as 26 additional …

Anti-Gd2 Etoposide-Loaded Immunoliposomes For The Treatment Of Gd2 Positive Tumors, Brandon S. Brown

Dissertations and Theses (Open Access)

Systemic chemotherapeutics remain the standard of care for most malignancies even though they frequently suffer from narrow therapeutic index, poor serum solubility, and off-target effects. Monoclonal antibodies that specifically bind antigens overexpressed on many tumors such as the ganglioside, GD2, can be conjugated to drug-loaded liposomes to create a targeted drug delivery system. In this study, we have encapsulated etoposide, a topoisomerase inhibitor effective against a wide range of cancers, in surface modified liposomes decorated with anti-GD2 antibodies. We characterized the properties of the liposomes using a variety of methods including dynamic light scattering, electron microscopy, and Fourier transformed infrared …

Phage Display Library Screening For Psa-/Lo Prostate Cancer Cell-Binding Peptides, John R. Moore

Dissertations and Theses (Open Access)

Prostate cancer (PCa) is one of the leading malignancies affecting men worldwide. Our lab focuses on understanding the molecular mechanisms underlying prostate carcinogenesis and developing therapeutics that target the cells responsible for driving PCa and mediating therapy resistance. My master thesis research employs a phage display library screening technology aiming to identify peptides that preferentially home in to undifferentiated PCa cells, which our lab has previously demonstrated to be intrinsically resistant to castration.

There is now evidence that a population of cells in PCa possesses characteristics associated with stem cells; these cells are referred to as cancer stem cells (CSCs). …

Design, Synthesis And Development Of Transporter Targeting Agents For Image-Guided Therapy And Drug Delivery, Ning Tsao

Dissertations and Theses (Open Access)

The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with ^99mTc and ⁶⁸Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. In vitro stability assessment showed both ^99mTc-N4amG and ^99mTc-GP were stable up to 6 hours, whereas ⁶⁸Ga-GP was stable up to 2 hours. Cell culture studies …

Stimulation Through Tlr4 Increases Fviii Inhibitor Formation In A Mouse Model Of Hemophilia A, Claire K. Holley

Dissertations and Theses (Open Access)

Hemophilia A is a clotting disorder caused by functional factor VIII (FVIII) deficiency. About 25% of patients treated with therapeutic recombinant FVIII develop antibodies (inhibitors) that render subsequent FVIII treatments ineffective. The immune mechanisms of inhibitor formation are not entirely understood, but circumstantial evidence indicates a role for increased inflammatory response, possibly via stimulation of Toll-like receptors (TLRs), at the time of FVIII immunization. I hypothesized that stimulation through TLR4 in conjunction with FVIII treatments would increase the formation of FVIII inhibitors. To test this hypothesis, FVIII K.O. mice were injected with recombinant human FVIII with or without concomitant doses …

Increased Geranylgeranylated K-Ras Contributes To Antineoplastic Effects Of Farnesyltransferase Inhibitors., Mandy A. Hall

Dissertations and Theses (Open Access)

The Ras family of small GTPases (N-, H-, and K-Ras) is a group of important signaling mediators. Ras is frequently activated in some cancers, while others maintain low level activity to achieve optimal cell growth. In cells with endogenously low levels of active Ras, increasing Ras signaling through the ERK and p38 MAPK pathways can cause growth arrest or cell death. Ras requires prenylation – the addition of a 15-carbon (farnesyl) or 20-carbon (geranylgeranyl) group – to keep the protein anchored into membranes for effective signaling. N- and K-Ras can be alternatively geranylgeranylated (GG’d) if farnesylation is inhibited but are …