Medicine and Health Sciences Commons^™

Understanding Molecular Mechanisms Of Glioblastoama Resistance To Design Novel Combinatorial Therapies, Amber B. Jones

All ETDs from UAB

Treatment options for the universally lethal brain tumor, glioblastoma (GBM), are severely limited and often unsuccessful in fully eradicating the disease. Extremely aggressive in nature, GBM cells often implore suppressive mechanisms to evade therapeutic detection which aids in the dismal 15-month median survival rate. Facilitating disease severity and more importantly, disease recurrence, are the immunosuppressive and chemoresistant phenotypes of GBM cells. Specifically, the DNA alkylating agent, temozolomide (TMZ) possesses lymphodepleting properties shunting robust immune cell infiltration into an immunologically cold tumor microenvironment. Additionally, through inherent or acquired mechanisms, GBM tumors commonly become resistant to the DNA damaging effects of TMZ …

Chemotherapy-Induced Pdl-1 Expression In Cancer-Associated Fibroblasts Promotes Chemoresistance In Nsclc, Gayathri Heenatigala Palliyage

Graduate Theses, Dissertations, and Problem Reports

A cure for cancer is out of reach for most patients due to chemoresistance. Cancer-associated fibroblasts (CAFs), one of the most abundant types of stromal cells in the tumor microenvironment, are known to provide functional and structural support for tumor progression. These cells also play a role in cancer chemoresistance, but a detailed understanding of the process, particularly in chemoresistant lung cancer, is lacking. In this study, we investigated programmed death-ligand 1 (PDL-1) as a potential biomarker for CAF-induced chemoresistance and evaluated its role and underlying mechanisms of chemoresistance in non-small cell lung cancer (NSCLC). We demonstrated that chemotherapy-stimulated CAFs …

Restoring The Sphingolipid Balance In Glioblastoma, Cyntanna C. Hawkins

All ETDs from UAB

Glioblastoma (GBM) is a highly aggressive brain tumor with a median survival of 15 months even with standard of care—surgical resection, radiotherapy, and chemotherapy. Two of the key characteristics contributing to this malignancy are its highly invasive phenotype and resistance to the chemotherapy, temozolomide (TMZ). We, and others, have identified the sphingolipid balance as a driver of these phenotypes with dysregulated sphingolipid metabolism seen in GBM patient samples. The ceramidases, specifically acid ceramidase (ASAH1), mediate the balance between ceramides and sphingosine-1-phosphate (S1P). ASAH1 breaks down ceramides ultimately forming S1P. While ceramides induce cell death, S1P promotes migration and cell survival. …

Secreted Mucin 5ac-Mediated Epithelial And Stromal Modulations Augment Pancreatic Cancer Aggressiveness, Koelina Ganguly

Theses & Dissertations

The mucosal layer that shields the epithelium of the body cavities is made up of high molecular weight, heavily glycosylated proteins called mucins that are broadly categorized into transmembrane and secreted members. Aberrant expression of secreted mucin MUC5AC has been implicated in lung, stomach, and colon cancer pathologies. MUC5AC is expressed de novo in the pancreas upon oncogenic insult, and its abundance in pancreatic tumor and circulation correlates to disease progression. However, few studies have explored beyond the diagnostic and prognostic significance of MUC5AC in pancreatic cancer (PC).

In this dissertation, we sought to investigate the mechanistic contribution of MUC5AC …

A Screen For Peptides Targeting Chemoresistant Metastatic Triple-Negative Breast Cancer, Shraddha Subramanian

Dissertations & Theses (Open Access)

Cancer metastasis is the principal cause of most cancer-associated morbidities. While radiotherapy, hormone therapy, and novel therapeutic strategies, including immunotherapy, have shown promise in inhibiting tumor growth, chemotherapy remains the mainstay in the clinical management of metastatic progression. This is often the case in triple-negative breast cancer (TNBC), an aggressive breast cancer subtype where tumorigenesis is independent of HER-2, progesterone, or estrogen receptor expression. Despite improving TNBC prognosis, recent studies report that after chemotherapy administration, TNBC drug-tolerant tumor cell survival, relapse, and metastatic dissemination may be promoted. Overcoming drug resistance exhibited by metastatic tumor cells is a challenge owing to …

Mitochondria Imaging And Targeted Cancer Treatment, Tinghan Zhao

Dissertations

Mitochondria are essential organelles as the site of respiration in eukaryotic cells and are involved in many crucial functions in cell life. Dysfunction of mitochondrial metabolism and irregular morphology have been frequently found in human cancers. The capability of imaging mitochondria as well as regulating their microenvironment is important both scientifically and clinically. Mitochondria penetrating peptides (MPPs), certain peptides that are composed of cationic and hydrophobic amino acids, are good candidates for mitochondria targeting. Herein, a novel MPP, D-argine-phenylalanine-D-argine-phenylalanine-D-argine-phenylalanine-NH₂ (rFrFrF), is conjugated with a rhodamine-based fluorescent chromophore (TAMRA). The TAMRA-rFrFrF probe exhibits advantageous properties for long-term mitochondria tracking of …

St6gal-I Mediated Sialylation Promotes Pancreatic Ductal Adenocarcinoma Progression And Chemoresistance, Asmi Chakraborty

All ETDs from UAB

ST6Gal-I adds α2-6 sialic acids to select N-glycosylated cell surface receptors, thereby modulating receptor function and intracellular signaling. ST6Gal-I is upregulated in various carcinomas and confers cancer stem cell (CSC) properties evidenced by tumorspheroid growth, chemoresistance and tumor initiating potential. In pancreatic ductal adenocarcinoma (PDAC), ST6Gal-I conferred gemcitabine resistance by abrogating DNA damage and altering expression levels of gemcitabine metabolism genes. Further, ST6Gal-I promoted resistance to chronic gemcitabine treatment. Additionally, metastatic clones of a PDAC cell line had increased ST6Gal-I expression and ST6Gal-I knockdown enhanced gemcitabine sensitivity. To investigate the physiological consequences of ST6Gal-I in PDAC, murine models were used. …

Role Of Sox9 In Cancer Stem Cell Regulation In Lung Cancer Chemoresistance And Particle-Induced Carcinogenesis, Maria Voronkova

Graduate Theses, Dissertations, and Problem Reports

Lung cancer is a leading cause of cancer-related death worldwide. Every year it claims more lives than other common malignancies, breast, prostate, and colorectal cancers, combined. And despite recent improvements in disease diagnostics and treatment, drug resistance and tumor relapse remain major contributors to low patient survival. Both issues have been largely attributed to the existence of cancer stem-like cells (CSCs) or tumor initiating cells (TICs). CSCs are a small cell population within heterogeneous tumors that is inherently resistant to apoptosis, chemo- and radiation therapy. Thus, it is critical to elucidate CSC-specific signaling pathways and identify early biomarkers for therapeutic …

Functional And Mechanical Role Of Splice Variant Of Mucin4 (Muc4/X) And Trefoil Factors In Pancreatic Cancer Pathogenesis, Rahat Jahan

Theses & Dissertations

Pancreatic Cancer (PC) is one of the vicious cancers as it ranks third in the race of leading cause of cancer-related death. Lack of early diagnostic marker, poor understanding of molecular mechanism of the disease and failure to conventional chemotherapy makes this disease dreadful.

Mucin 4 (MUC4), a high molecular weight glycoprotein is one of the top differentially expressed molecules in PC while not expressed in normal pancreas. Accumulating evidence from our lab suggested its tumorigenic role in PC by increasing cell proliferation, invasion, chemotherapy resistance, tumor growth, and metastasis. Previously, our lab and other has identified 24 different splice …

Rna-Seq Reveals Transcriptomic Program Associated With Stemness In Taxane Resistant Prostate Cancer, Christina K. Cajigas-Du Ross

Loma Linda University Electronic Theses, Dissertations & Projects

There is no cure for advanced prostate cancer (PCa), and taxane chemotherapy is the only treatment option once other therapies have failed. However, this is problematic since all patients eventually develop chemoresistance. Emerging treatments for advanced PCa have shown promise at the benchside, but clinical trials have not resulted in newly approved drugs due in part to redundant survival pathways utilized by prostate tumor cells to maintain therapy-resistance. Using RNAsequencing—an innovative approach for quantifying gene expression changes—this dissertation sought to elucidate chemoresistance-associated molecular pathways as a catalyst to develop new therapeutic targets. Results revealed a differential upregulation of stemness-associated genes …

Genomic Evolution Of Chemoresistance In Triple-Negative Breast Cancer Delineated By Single Cell Sequencing, Charissa Kim

Dissertations & Theses (Open Access)

Triple-negative breast cancer (TNBC) is an aggressive subtype that displays extensive intratumor heterogeneity and frequently (46%) develops resistance to neoadjuvant chemotherapy (NAC). Currently, the genomic basis of chemoresistance remains poorly understood. An important question is whether resistance to chemotherapy is driven by the selection of rare pre-existing subclones with genomic mutations and transcriptional programs that confer resistance to chemotherapy (adaptive resistance) or by the spontaneous induction of new mutations and expression changes that confer a resistant phenotype (acquired resistance). To investigate this question we applied single cell DNA and RNA sequencing methods and deep-exome sequencing to longitudinal time-point samples collected …

The Role Of Pim Kinases In Hepatoblastoma Tumorigenicity, Stem Cell-Like Cancer Cell Maintenance, And Chemoresistance, Laura Lee Stafman

All ETDs from UAB

Hepatoblastoma is the most common primary liver malignancy in children. Despite increasing incidence, treatment has not changed significantly in the past 20 years, making the need for novel therapeutics imperative. Proviral Integration site for Moloney murine leukemia virus (PIM) kinases are a family of serine/threonine kinases that have been implicated in multiple other cancer types including the adult liver cancer, hepatocellular carcinoma. Emerging evidence has begun to elucidate a role for PIM kinases in stem-cell like cancer cells (SCLCCs). This subpopulation of cells is thought tobe responsible for tumor maintenance, recurrence, metastasis, and chemoresistance. Chemoresistance is a significant barrier to …

An Invasive Tumor Cell Subpopulation As A Therapeutic Target In Breast Cancer, Tahereh Vakili

Electronic Thesis and Dissertation Repository

Tumor heterogeneity and lack of targeted therapies are major hurdles in triple-negative breast cancer (TNBC) management. Elevated hyaluronan (HA) is a prognostic factor for poor outcome in TNBC. The TNBC MDA-MB-231 cell line contains highly metastatic but slow growing subpopulations that bind high levels of HA. I show these subpopulations express elevated HAS2, RHAMM and PGA3, and are more resistant to doxorubicin but more sensitive to MEK1 targeted therapy than parental cells or low HA binding subpopulations. Databank mining show HAS2, RHAMM, and PGA3 are significantly associated with chemotherapy-treated BCa. Knockout of RHAMM using CRISPR/Cas9 gene editing reduced localization of …

Targeting Ledgf/P75 To Sensitize Chemoresistant Prostate Cancer Cells To Taxanes, Leslimar Rios-Colón

Loma Linda University Electronic Theses, Dissertations & Projects

Prostate cancer (PCa) is the second most diagnosed cancer in males. This disease disproportionately affects African American men, with a higher incidence and mortality compared to other ethnic/racial groups. An aging male population and the complexity of addressing the health disparities associated with this disease puts PCa into the spotlight due to its serious public health implications and the imminent fiscal challenge over the next decades. Chronic prostate inflammation resulting in activation of stress and prosurvival pathways contribute to disease progression and the development of chemoresistance. Lens epithelium-derived growth factor p75 (LEDGF/p75) is a stressresponse protein that promotes cellular survival …

C-Abl And Arg Drive Cancer Chemoresistance Via Activation Of Multiple Signaling Pathways, Jonathan Thomas Sims

Theses and Dissertations--Pharmacology and Nutritional Sciences

Despite 35 years of clinical trials, there has been little improvement in one-year survival rates with any chemotherapeutic regimen for the treatment of metastatic melanoma due to resistance to all known agents. Regardless of advances in detection and prevention, diagnosis of metastatic disease remains a death sentence. Resistance mechanisms, including aberrant kinase signaling and drug transport pumps, indicate a need for identification of other therapeutic targets that impinge upon multiple signaling pathways. The Abl family of non-receptor tyrosine kinases (c-Abl, Arg) has been indicted as a causative force in leukemia for more than three decades; however, their role in solid …

Prognostic Significance Of Xct Polymorphisms And Expression In Patients With Advanced Pancreatic Cancer Treated With Chemotherapy, Tzu-Chuan Jane Huang Md

Dissertations & Theses (Open Access)

The plasma membrane x_c^- cystine/glutamate transporter mediates cellular uptake of cystine in exchange for intracellular glutamate and is highly expressed by pancreatic cancer cells. The xCT gene, encoding the cystine-specific xCT protein subunit of x_c^-, is important in regulating intracellular glutathione (GSH) levels, critical for cancer cell protection against oxidative stress, tumor growth and resistance to chemotherapeutic agents including platinum. We examined 4 single nucleotide polymorphisms (SNPs) of the xCT gene in 269 advanced pancreatic cancer patients who received first line gemcitabine with or without cisplatin or oxaliplatin. Genotyping was performed using Taqman real-time PCR …