Cancer Biology Commons^™

The Effects Of Panobinostat On Cellular Signaling Pathways And How It Relates To Antitumor Activities In Ewing Sarcoma Cancer Cells, Crystal Valenzuela, Andrew Martini, Hannah Navarro, Mario Flores, Terry Jo Shackleford

Cell and Molecular Methods

Ewing sarcoma is a rare and aggressive cancer that primarily affects the bones and surrounding soft tissues, most commonly in children and young adults. Although the exact etiology remains unclear, a well-documented cause involves a chromosomal translocation resulting in the fusion of the EWSR1 and FLI1 genes. This fusion produces abnormal proteins that disrupt normal gene expression, cell signaling, and RNA processing, contributing to tumorigenesis. Prognosis varies significantly depending on the extent of metastasis, with 5-year survival rates ranging from 82% in localized cases to 39% in metastatic cases. Standard treatments include chemotherapy typically involving vincristine, doxorubicin, etoposide, and cyclophosphamide—surgical …

The Effects Of Hispidin And Eribulin Mesylate On Cell Proliferation Of Ewing Sarcoma Cell Lines, Elena Mares, Angelina Juarrita, Sierra Munoz, Terry Jo Shackleford

Cell and Molecular Methods

Ewing sarcoma is a type of cancer that targets the cells within bones and soft tissue and is most prevalent in younger populations. It is important to look at this specific cancer because there is no cure yet, and the risks increase, even after a patient has completed their treatment. We hypothesize that if we treat Ewing sarcoma cell lines with natural compounds, specifically Hispidin and Eribulin Mesylate, then the cell lines will decrease in cell viability and there will be an increase in apoptosis of the cancerous cell lines. We performed a series of experiments, which included IC50 analysis, …

Neurodevelopmental And Environmental Mechanisms Of Invasion, Proliferation, And Tumor Cell Fate Specification In Glioblastoma, Bianca Lynn Myers

Biomedical Sciences ETDs

Glioblastomas (GBMs) are the most aggressive primary brain tumors, and despite over 50 years of research efforts, the median survival remains at 14 months post-diagnosis. The current standard of care consists of maximal surgical resection radiotherapy with concurrent chemotherapy using temozolomide. However, the highly proliferative and invasive nature of GBM cells renders total resection nearly impossible as tumor cells invade the surrounding healthy tissue. The molecular and environmental drivers of these tumorigenic phenotypes are largely unknown. Here, we demonstrate that the neurodevelopmental transcription factor ASCL1 enhances tumor cell proliferation and invasion while activating the expression of a neural stem cell …

Cholestasis And Fluid Flow Are Biomechanic Regulators Of Cholangiocarcinoma Progression, Andrew Oleksijew

Theses & Dissertations

Cholestasis, altered or absent bile flow, is associated with poor survival in patients with cholangiocarcinoma, an aggressive cancer of the biliary epithelium. Changes in bile flow often result in stricture or obstruction. Experimental cholestasis promoted tumor growth and progression. However, studies are needed that directly assess the mechanical interaction between bile flow, or bile shear stress, and cholangiocarcinoma signaling. We hypothesized that cholestasis and absent bile shear stress activated cancer signaling and increased aggressive cellular behaviors such as proliferation and migration. Fluid shear stress approximating bile flow was applied by orbital culture plate method and compared to identical static culture …

Validating The Ability Of Iag933 To Block The Interaction Of Yap1 And Tead In Ovarian Cancer Cells, Alex Sage

Theses & Dissertations

Ovarian cancer is the most common and deadliest gynecologic malignancy. Approximately 40% of ovarian cancer patients exhibit chemoresistance after receiving initial treatment in the form of neoadjuvant chemotherapy or interval debulking surgery, of which YAP1 (Yes-associated protein 1) has been implicated in enhancing the resistance of ovarian cancer to Cisplatin and Taxol.^1,2. This highlights the need to develop new therapeutic strategies that target the Hippo pathway to overcome resistance to traditional therapies.

YAP1 is a protein that acts as a transcription coregulator, promoting the transcription of genes involved in cellular proliferation and suppressing apoptotic genes. It is a …

Novel Combination Therapies For Estrogen Receptor-Positive Breast Cancer Driven By Rational Molecular Mechanisms, Anneka Lila Johnson

Dartmouth College Ph.D Dissertations

Breast cancer (BC) is the most common non-keratinocyte cancer diagnosed in women in the United States with approximately 300,000 new cases diagnosed each year. Despite a myriad of treatment options, BC remains the second-most deadly cancer. Estrogen receptor-positive (ER+) BC comprises 60-70% of BC diagnoses and is treated with endocrine therapies that limit ER signaling. Despite endocrine therapy options, ~1/3 of patients experience recurrence within 10-20 years of diagnosis. Novel therapeutic strategies are required to limit BC recurrence-related morbidity and mortality.

Radiotherapy is used as an adjuvant treatment for ER+ BC patients prior to the use of endocrine therapy. Radiation …

Unpaired Virtual Histological Staining Of Tissue From Autofluorescence Using Regularized Cycle-Consistent Adversarial Networks, Zhesi Wen

Theses and Dissertations

We present a regularized CycleGAN with a Dense Residual U-Net to virtually stain autofluorescence images of tissue into H&E-like images. Our method outperforms standard architectures, reduces artifacts, and achieves superior FID scores, enabling efficient, label-free, and accurate digital pathology for unpaired datasets using multi-channel fluorescence inputs.

Ks151 Synergizes With Venetoclax And Abt-737 In Aml: Efficacy In Both Flt3-Wildtype And Flt3-Mutant Models, Sahil Jethi, Arnold Rojas, Omar S. Al-Odat, Krishne Gowda, Subash C. Jonnalagadda, Manoj Pandey

Rowan-Virtua Research Day

Acute myeloid leukemia (AML) is the most common leukemia in adult patients, with a 5-year survival rate of less than 30 percent. Therefore, more effective therapeutic strategies are required to prolong the survival of AML patients. Importantly, anti-apoptotic proteins, especially B-cell lymphoma 2 (Bcl-2), overexpression in AML is associated with uncontrolled growth as well as chemoresistance. Unsurprisingly, Bruton’s tyrosine kinase (BTK) overexpresses in AML and associated with poor prognosis and chemoresistance. The FDA-approved BTK inhibitor, ibrutinib, has been successful in treating other hematologic malignancies, but a proportion of patients relapse mainly because of acquired mutations at Cys481Ser (C481S) in the …

Identifying Novel Molecular Targets To Induce Ferroptosis In Drug-Tolerant Cancer Cells Through Computational Modeling, Haris J. Rana

Biological Sciences Undergraduate Honors Theses

Ferroptosis is an iron-dependent, reactive oxygen species (ROS)-driven form of regulated cell death in which the cell membrane is degraded by lipid peroxidation. It is regulated by multiple enzymes, such as glutathione peroxidase 4 (GPX4), which prevents membrane degradation by reducing lipid peroxides and protecting cells from oxidative damage. When inhibitors like RSL3 target GPX4, lipid peroxides build up, and toxic ROS compromises membrane integrity. Traditional anticancer treatments, such as most chemotherapies, aim to eliminate tumor cells by damaging DNA and triggering apoptosis. However, resistance to apoptosis is a “hallmark of cancer,” often resulting in treatment failure. As a distinct …

Differential Regulation Of The Prkacaa Promoter In Zebrafish Melanoma Cell Lines, Maria Fiuk

Theses, Dissertations and Culminating Projects

The Inducible cAMP Early Repressor (ICER) comprises a group of isoforms that function as transcription factors within the cyclic AMP (cAMP) signaling pathway. These isoforms are encoded by the cAMP Response Element Modulator (CREM) gene. The cAMP signaling pathway and its associated transcriptional regulators have been implicated in the development of resistance to BRAF/MEK-targeted therapies in melanoma. Recent findings from our laboratory demonstrated that transgenic ICER expression in a zebrafish melanoma model promotes the formation of aggressive melanomas. Cell lines were established from tumors expressing ICER, as well as from control tumors expressing Green Fluorescent Protein (GFP). To begin characterizing …

Exploring Intracellular Signaling Responses To Ks18, A Potent Mcl-1 Inhibitor, In Multiple Myeloma, Emily Nelson, Omar S Al-Odat, Dhruti A. Brahmbhatt, Tulin Budak-Alpdogan, Subash Jonnalagadda, Manoj Kumar Pandey

Rowan-Virtua Research Day

Multiple myeloma (MM), a cancer of plasma B cells, is a hematological malignancy in which patients inevitably relapse and develop drug resistance. Mcl-1, a member of the anti-apoptotic subgroup of Bcl-2 family proteins, plays a critical role in the progression of multiple myeloma and contributes significantly to drug resistance. Elevated Mcl-1 expression is observed in approximately 52% of MM patients at diagnosis, increasing to 81% at relapse. Given its driving role in disease progression and therapy resistance, Mcl-1 inhibition has emerged as a promising therapeutic target, prompting ongoing research into the development and clinical evaluation of Mcl-1 inhibitors, particularly for …

Accelerated Tumor Growth And Lymphatic Spread Of Transplantable Melanomas In Tumor Necrosis Factor(Tnf)-Transgenic Mice, Catherine F. Alapatt, Robert Hughes, Roger Sheffmaker, Gillian Mcguire, Daniel Deegan, Igor Kuzin, Andrea Bottaro

Rowan-Virtua Research Day

Melanoma is the fifth most common cancer among American adults, with significant morbidity and mortality at 5 years remaining >60% for patients with stage IV disease. The malignancy is due to the transformation of melanocytes, with one of the major risk factors being ultraviolet light exposure. Although as many as one in five human cancers have been linked to chronic inflammation, the role of inflammatory signals in melanoma growth and metastasis remains poorly understood.

Tumor necrosis factor (TNF)-transgenic (TNFtg) mice are a well-established model of chronic systemic inflammation, with involvement of joints and other organ systems. To assess the effect …

Examining The Molecular Mechanisms Of Glucagon-Like Peptide-1 Receptor Agonists In Cancer Cell Biology, Oliver G. Sabet

Honors Scholar Theses

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are synthetic analogs of glucagon-like peptide-1 (GLP-1) used to treat obesity and diabetes by reducing blood glucose levels and appetite. While early rodent studies suggested a link between GLP-1RAs and thyroid cancer pathogenesis, evidence in humans remains inconclusive, with randomized controlled trials not supporting that link. Due to the rapid, widespread use of these drugs, concerns have expanded to other obesity-associated cancers, with conflicting findings on their role in cancer progression. With this contradictory evidence in a novel intersection of obesity medicine and oncology, this literature review aims to summarize current understandings between GLP-1-RAs and …

A Nano-Scale Approach To Controlled Apoptosis In Brain Cancer Through Magneto-Mechanical Actuation, Sakura Rieck

Biological Sciences Undergraduate Honors Theses

In this study, we investigate the effects of cell therapy and magneto-mechanical actuation (MMA) to treat glioblastoma (U87). MMA approach employs super low-frequency alternating magnetic fields (AMF) to actuate intracellular PEGylated superparamagnetic iron oxide nanoparticles (PEG-SPIONs). Magnetic forces are translated into mechanical agitation on PEG-SPIONs, which can disrupt key cellular components. We explored two ways in which the MMA approach can be used to combat cancer growth. First, we investigated MMA directly in U87 cells. Preliminary observations indicate that PEG-SPIONs are intracellularly taken up by the U87 cells via micropinocytosis. Cell-counting kit-8 toxicity assays revealed a cytotoxic effect of MMA …

Which Costimulatory Domains In Chimeric Antigen Receptor T Cells Induce Cytokine Responses That Are Linked To A More Toxic Car T Cell Therapy In Acute Lymphocytic Leukemia?, Elisabeth Cohen

Longwood Senior Thesis Proposal

No abstract provided.

Translation Of The Carcinogenic Dna Breakage-Repair Inhibition Mechanism For Hexavalent Chromium To Its Key Targets: Lung Epithelial Cells, Lung Tissue And Impacts On The Genome., Idoia Meaza Isusi

Electronic Theses and Dissertations

Lung cancer is the leading cause of cancer death worldwide. Hexavalent chromium [Cr(VI)] is a human lung carcinogen with widespread occupational and environmental exposure. Despite the known health risks, how Cr(VI) causes lung cancer remains unclear. This dissertation investigates the mechanisms of Cr(VI)-induced carcinogenesis. Cr(VI) causes DNA damage, specifically DNA double strand breaks, and inhibits homologous recombination repair, a high-fidelity repair pathway. Unrepaired DNA double strand breaks or those repaired through error-prone pathways, progress to chromosomal damage, and chromosome instability. The latter is a common characteristic of Cr(VI)-exposed cells, and a hallmark of lung cancer. Although the mechanism of Cr(VI)-induced …

Fc Gamma Receptors Facilitate Antigenic Modulation Of Lilrb4 And Function As Predictive Biomarkers In Acute Monocytic Leukemia, Joshua Morse

Dissertations and Theses (Open Access)

Acute monocytic leukemia (monocytic AML) is a subtype of AML marked by a proliferation of abnormal monoblasts. This subtype represents approximately 10% of AML cases. The prognosis of monocytic AML is poor, with a 5-year survival of ~30%. Most patients are diagnosed at an age when they are unlikely to survive first-line non-targeted cytotoxic chemotherapy as a bridge to hematopoietic stem cell transplant (HSCT). Even patients who achieve remission commonly relapse. This population of patients would greatly benefit from precision-targeted therapies but currently there are none approved for monocytic AML.

Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immune checkpoint expressed …

Targeting Bard1 Suppresses A Myc-Dependent Transcriptional Program And Tumor Growth In Pancreatic Ductal Adenocarcinoma, Sohum Patel, Eleanor Jenkins, Rutuj P. Kusurkar, Sherry Lee, Wei Jiang, Avinoam Nevler, Matthew Mccoy, Michael J. Pishvaian, Rosalie C. Sears, Jonathan R. Brody, Charles J. Yeo, Aditi Jain

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers demanding better and more effective therapies. BARD1 or BRCA1-Associated -Ring Domain-1 plays a pivotal role in homologous recombination repair (HRR). However, its function and the underlying molecular mechanisms in PDAC are still not fully elucidated. Here, we demonstrate that BARD1 is overexpressed in PDAC and its genetic inhibition suppresses c-Myc and disrupts c-Myc dependent transcriptional program. Mechanistically, BARD1 stabilizes c-Myc through ubiquitin-proteasome system by regulating FBXW7. Importantly, targeting BARD1 using either siRNAs or CRISPR/Cas9 deletion blocks PDAC growth in vitro and in vivo, without any signs of toxicity to mice. …

Developing A Small Molecule To Inhibit Hsf1 Expression In Cancer And Evaluating Natural Genetic Variation In Small Molecule Toxicity., Michaela Kendal Foley

Theses and Dissertations

Each year cancer affects nearly 20 million people worldwide and genetic differences across populations can impact cancer onset and progression. Specifically, tumors with high levels of HSF1, the master regulator of the cytoprotective heat shock response (HSR), are correlated with poor patient outcomes in multiple cancers such as prostate, breast, and melanoma. Subsequently, the development of pharmacological inhibitors of HSF1 represents a promising strategy for anticancer therapeutics. Using a luciferase-based transcriptional reporter, two small molecule libraries were screened for inhibitors of HSF1 expression in human embryonic kidney cells, yielding ten compounds that decrease HSF1 expression. To identify if cancer lines …

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 …

Therapeutic Vulnerabilities Of Venetoclax Resistant Chronic Lymphocytic Leukemia And Novel Treatment Strategies Targeting Bcl2/Bcl-Xl, Daisy Y. Diaz-Rohena

Dissertations and Theses (Open Access)

Despite major advancements in the management of chronic lymphocytic leukemia (CLL), drug resistance remains a major challenge. CLL resistant to venetoclax (VEN) have limited available therapeutic options, especially when the leukemic cells have dysfunctional p53 and have relapsed on Bruton’s tyrosine kinase inhibitors (BTKi). The broad hypothesis of this thesis is that VEN-relapsed CLL exhibits altered dependence on BCL2 family members, which can be exploited for therapeutic benefit. I profiled 28 CLL samples collected from 15 patients either at baseline or at relapse following VEN treatment, which was administered in combination with a BTKi or sequentially as monotherapy after a …

Ascl2 Positive Tumor Cells Modulate The Response Of Metastatic Colorectal Cancer To Mapk-Targeting Therapy, Oscar Eduardo Villarreal

Dissertations and Theses (Open Access)

Colorectal cancer (CRC) is the second leading cause of cancer related deaths with nearly a quarter of patients presenting with metastatic disease at the time of their diagnosis. Therapeutic management of metastatic CRC continues to be a major challenge due to therapy resistance and disease heterogeneity. Due to its central role in tumorigenesis, CRC is commonly treated with MAPK pathway inhibitors (MAPKi). However, clinical trials repeatedly demonstrates that durability of benefit is short-lived in many patients. While genomic mechanisms of acquired resistance have been described, they explain a minority of patients, and further research is needed to determine the underlying …

Identification Of Mitochondrial Defects And Metabolic Consequences In Lynch Syndrome-Related Endometrial Cancer, Mikayla Bowen

Dissertations and Theses (Open Access)

Lynch syndrome (LS), defined by mutations in DNA mismatch repair genes including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Mismatch repair deficiency (MMRd) causes hypermutability, which is assumed to be the main driver of LS-related EC development. However, incomplete penetrance of EC development in women with LS suggests that other modulators are at play. The broad hypothesis of this dissertation is that MMRd causes consequences beyond hypermutability to impact LS-related EC development. Recent studies utilizing our lab’s Msh2-deficient mouse model for LS-EC revealed mitochondrial dysfunction in EC pathogenesis. This new insight led to the …

Developing Novel Therapies Targeting The Tumor Microenvironment Of Aggressive Breast Cancer, Lan T H Phi

Dissertations and Theses (Open Access)

Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are the most aggressive breast cancer subtypes. The tumor microenvironment (TME) is critical in driving these aggressive breast cancers' clinical phenotype and aggressiveness. Therefore, we explored novel actionable targets and complementary therapies targeting the TME to improve the outcomes of patients with these cancers.

In this thesis, we identified AXL as a potential therapeutic target in IBC due to its role in generating an immunosuppressive TME. Indeed, inhibiting the AXL pathway suppresses IBC tumor growth and reduces M2 macrophage populations in various mouse models. Mechanistically, AXL facilitates the polarization of M2 …

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 …

Relationship Between Processing Body Formation, Epithelial-To-Mesenchymal Transition, And Invasion In Lung Adenocarcinoma, Amanda Warner

Dissertations and Theses (Open Access)

Lung cancer is the leading cause of cancer-related deaths in the United States, largely due to its ability to metastasize. Epithelial-to-mesenchymal transition (EMT) is a process that enhances the ability of cells to lose their cell-cell contacts, invade, and enter the blood stream which are essential during metastasis. Many transcriptional gene programs are altered during EMT such as activation of mesenchymal transcription factors, like ZEB1, and enhanced response to the TGFβ1 cytokine. In oncogenic contexts, TGFβ1 enhances the formation of processing-bodies (P-bodies) where P-body proteins are required for invasion in multiple cancerous cell lines. P-bodies are a type of ribonucleoprotein …

Overcoming Resistance To Cdk4/6-Targeted Therapy Using Jak2/Stat3 Inhibitor In Triple-Negative Breast Cancer, Chuling Zhuang

Dissertations and Theses (Open Access)

Breast cancer is the most common type of cancer diagnosed in women, with nearly 30% of cases becoming metastatic accounting for over 90% of breast cancer-related deaths. Among different breast cancer subtypes, triple-negative breast cancer (TNBC) has the worst prognosis and the highest propensity to metastasize. However, TNBC patients have limited treatment options due to their lack of actionable drug targets while therapeutic resistances result in high rates of recurrence and metastasis. Cyclin-dependent kinase 4 and 6 (CDK4/6) are major cell cycle regulators that control G1 to S phase transition and aberrant hyperactivation of the CDK4/6 pathway results in uncontrolled …

Harnessing The Immunomodulatory Potential Of Radiofrequency Ablation To Improve Therapeutic Outcomes In Pancreatic Ductal Adenocarcinoma, Bhumi Maniyar

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) continues to rank among the most lethal cancers with poor prognosis. PDAC is characterized by a thick desmoplastic stroma, severe immunological suppression, and resistance tostandard treatments. The need for innovative therapeutic approaches is highlighted by the tumor microenvironment's (TME) critical role in promoting disease development and reducing the effectiveness oftreatment. A promising locoregional treatment that can induce tumor necrosis and modify the TME is endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA). However, there is still minimal understanding around its wider impact on stromal remodeling and immunological activation. This study investigates the immunomodulatory effects of RFA combined with neoadjuvant …

Role Of Mir-4732-3p In Breast Cancer Brain Metastasis And Brain Metastatic Tumor Microenvironment, Munazza Samar Khan

Dissertations and Theses (Open Access)

In this study, we aimed to identify microRNAs (miRNAs) that may play important roles in breast cancer brain metastasis (BCBM). To this end, we conducted miRNA-sequencing of extracellular vesicles isolated from the serum samples of 6 BCBM patients and 8 Stage I/II/III breast cancer patients, and identified 49 circulating miRNAs that were upregulated in BCBM patients compared to Stage I/II/III breast cancer. Upon further analysis, we identified miR-4732-3p to be upregulated in brain-tropic triple-negative breast cancer (TNBC) cell lines, compared to parental lines. MiR-4732-3p overexpression increased metastatic properties of TNBC cells, including proliferation, migration, invasion, and maintenance of a mesenchymal …

Exploring The Immunologic Consequences Of Atrx Deficiency In Glioma, Benjamin Whitfield

Dissertations and Theses (Open Access)

ATRX is a key chromatin regulator that is frequently mutated across multiple cancer types. One of the most common ATRX-mutated tumor types is the adult-type glioma, IDH-mutant, Astrocytoma. It is known that ATRX mutation leads to increases in DNA damage, replication stress, and global epigenetic regulation at a cell level; however, less is known about the impact of ATRX mutation on immune signaling. Furthermore, little is known about the interaction of ATRX loss with gain-of-function mutations in IDH. In this paper we set out to explore the impact of ATRX loss on immune signaling in gliomas, both in the context …