Cancer Biology Commons^™

Hexavalent Chromium Induces Malignant Transformation Of Human Lung Bronchial Epithelial Cells Via Ros-Dependent Activation Of Mir-21-Pdcd4 Signaling, Poyil Pratheeshkumar, Young-Ok Son, Sasidharan Padmaja Divya, Lilia Turcios, Ram Vinod Roy, John Andrew Hitron, Lei Wang, Donghern Kim, Jin Dai, Padmaja Asha, Zhuo Zhang, Xianglin Shi

Center for Research on Environmental Disease Faculty Publications

Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with an increased risk of lung cancer. However, the mechanisms underlying Cr(VI)-induced carcinogenesis remain unclear. MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. Studies have shown that miR-21 exerts its oncogenic activity by targeting the tumor suppressor gene programmed cell death 4 (PDCD4). The present study examined the role of miR-21-PDCD4 signaling in Cr(VI)-induced cell transformation and tumorigenesis. Results showed that Cr(VI) induces ROS generation in human bronchial epithelial (BEAS-2B) cells. Chronic exposure to Cr(VI) is able to cause malignant transformation in BEAS-2B cells. Cr(VI) caused a significant increase of …

Klf4 Deletion Alters Gastric Cell Lineage And Induces Muc2 Expression, Tianxin Yu, Xi Chen, T. Lin, J. Liu, M. Li, W. Zhang, X. Xu, W. Zhao, M. Liu, Dana L. Napier, Chi Wang, B. Mark Evers, Chunming Liu

Markey Cancer Center Faculty Publications

Gastric cancer is one of the most common types of cancer in the world, particularly in underdeveloped countries. The mechanism of gastric cancer is less understood compared with other types of gastrointestinal (GI) cancers. Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor and is a potential tumor suppressor in GI cancers. In this study, we have generated two mouse models, Rosa-Cre;Klf4^fl/fl and Lgr5-Cre;Klf4^fl/fl. KLF4 was deleted by Rosa-Cre in the gastric epithelia cells or by Lgr5-Cre in the antral stem cells in the adult mice. KLF4 deletion resulted in increased proliferating cells and decreased pit mucous …

Identification Of Genes That Are Essential To Restrict Genome Duplication To Once Per Cell Division., Alex Vassilev, Chrissie Y. Lee, Boris Vassilev, Wenge Zhu, Pinar Ormanoglu, Scott E. Martin, Melvin L. Depamphilis

Biochemistry and Molecular Medicine Faculty Publications

Nuclear genome duplication is normally restricted to once per cell division, but aberrant events that allow excess DNA replication (EDR) promote genomic instability and aneuploidy, both of which are characteristics of cancer development. Here we provide the first comprehensive identification of genes that are essential to restrict genome duplication to once per cell division. An siRNA library of 21,584 human genes was screened for those that prevent EDR in cancer cells with undetectable chromosomal instability. Candidates were validated by testing multiple siRNAs and chemical inhibitors on both TP53+ and TP53- cells to reveal the relevance of this ubiquitous tumor suppressor …

The Roles Of Malt1 In Nf-Κb Activation And Solid Tumor Progression, Deng Pan

Dissertations and Theses (Open Access)

The transcription factor NF-κB plays a central role in many aspects of biological processes and diseases, such as inflammation and cancer. Although it has been suggested thatNF-κB is critical in tumorigenesis and tumor progression, the molecular mechanism by which NF-κB is activated in solid tumor remains largely unknown. In the current work, we focus on growth factor receptor-induced NF-κB activation and tumor progression, including epidermal growth factor receptor (EGFR)-induced NF-κB in lung cancer and heregulin receptor (HER2)-induced NF-κB in breast cancer. We found that Mucosa-associated lymphoma translocation protein 1 (MALT1), also known as paracaspase, is required for EGFR-induced NF-κB activation …

S100a4 Drives Non-Small Cell Lung Cancer Invasion, Associates With Poor Prognosis, And Is Effectively Targeted By The Fda-Approved Anti-Helminthic Agent Niclosamide, Rachel L. Stewart, Brittany L. Carpenter, Dava S. West, Teresa Knifley, Lili Liu, Chi Wang, Heidi L. Weiss, Tamas S. Gal, Eric B. Durbin, Susanne M. Arnold, Kathleen L. O'Connor, Min Chen

Markey Cancer Center Faculty Publications

S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular …

P-Rex1 Promotes Resistance To Vegf/Vegfr-Targeted Therapy In Prostate Cancer, Hira Lal Goel, Bryan Pursell, Leonard D. Shultz, Dale L. Greiner, Rolf A Brekken, Craig W. Vander Kooi, Arthur M. Mercurio

Molecular and Cellular Biochemistry Faculty Publications

Autocrine VEGF signaling is critical for sustaining prostate and other cancer stem cells (CSCs), and it is a potential therapeutic target, but we observed that CSCs isolated from prostate tumors are resistant to anti-VEGF (bevacizumab) and anti-VEGFR (sunitinib) therapy. Intriguingly, resistance is mediated by VEGF/neuropilin signaling, which is not inhibited by bevacizumab and sunitinib, and it involves the induction of P-Rex1, a Rac GEF, and consequent Rac1-mediated ERK activation. This induction of P-Rex1 is dependent on Myc. CSCs isolated from the PTEN^pc−/− transgenic model of prostate cancer exhibit Rac1-dependent resistance to bevacizumab. Rac1 inhibition or P-Rex1 downregulation increases the …

Autocrine Epiregulin Activates Egfr Pathway For Lung Metastasis Via Emt In Salivary Adenoid Cystic Carcinoma, Shuli Liu, Dongxia Ye, Dongliang Xu, Yueling Liao, Ling Zhang, Liu Liu, Wenwen Yu, Yanan Wang, Yue He, Jingzhou Hu, Wenzheng Guo, Tong Wang, Beibei Sun, Hongyong Song, Huijing Yin, Jingyi Liu, Yadi Wu, Hanguang Zhu, Binhua P. Zhou, Jiong Deng, Zhiyuan Zhang

Markey Cancer Center Faculty Publications

Salivary adenoid cystic carcinoma (SACC) is characterized by invasive local growth and a high incidence of lung metastasis. Patients with lung metastasis have a poor prognosis. Treatment of metastatic SACC has been unsuccessful, largely due to a lack of specific targets for the metastatic cells. In this study, we showed that epidermal growth factor receptors (EGFR) were constitutively activated in metastatic lung subtypes of SACC cells, and that this activation was induced by autocrine expression of epiregulin (EREG), a ligand of EGFR. Autocrine EREG expression was increased in metastatic SACC-LM cells compared to that in non-metastatic parental SACC cells. Importantly, …

Targeting Wnt/Β-Catenin Pathway In Hepatocellular Carcinoma Treatment, Valery Vilchez, Lilia M. Turcios, Francesc Marti, Roberto Gedaly

Surgery Faculty Publications

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug …

Mir-671-5p Inhibits Epithelial-To-Mesenchymal Transition By Downregulating Foxm1 Expression In Breast Cancer., Xiaohui Tan, Yebo Fu, Liang Chen, Woojin Lee, Yinglei Lai, M. Katayoon Rezaei, Sana Tabbara, Patricia Latham, Christine B Teal, Yan-Gao Man, Robert S. Siegel, Rachel F. Brem, Sidney W. Fu

Medicine Faculty Publications

MicroRNA (miRNA) dysfunction is associated with a variety of human diseases, including cancer. Our previous study showed that miR-671-5p was deregulated throughout breast cancer progression. Here, we report for the first time that miR-671-5p is a tumor-suppressor miRNA in breast tumorigenesis. We found that expression of miR-671-5p was decreased significantly in invasive ductal carcinoma (IDC) compared to normal in microdissected formalin-fixed, paraffin-embedded (FFPE) tissues. Forkhead Box M1 (FOXM1), an oncogenic transcription factor, was predicted as one of the direct targets of miR-671-5p, which was subsequently confirmed by luciferase assays. Forced expression of miR-671-5p in breast cancer cell lines downregulated FOXM1 …

Uncovering New Roles For The Aryl Hydrocarbon Receptor (Ahr) In Breast Cancer, Justin Kirk Tomblin

Theses, Dissertations and Capstones

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is responsive to many exogenous and endogenous ligands. AHR is of particular interest in cancer, and has been shown to play roles in tumor progression. As such, it has received growing attention as a possible chemotherapeutic target. Obesity increases the risk of breast cancer, complicates treatment of breast cancer, and stimulates the growth of larger, more aggressive mammary tumors. Many breast tumors in obese women are estrogen receptor (ER)-positive and, while targeting hormone receptors like ER is beneficial, many obese women see a recurrence of their cancer after standard …

Characterizing The Oncogenic Properties Of C-Terminal Binding Protein, Evan T. Sumner

Theses and Dissertations

The paralogous C-terminal binding proteins (CtBP) 1 and 2 are evolutionarily conserved transcriptional coregulators that target and disrupt the expression of several genes essential for multiple cellular processes critical to regulating tumor formation. CtBP’s ability to govern the transcription of genes necessary for apoptosis, tumor suppression, invasion/migration and EMT gives rise to its oncogenic activities. Both isoforms of CtBP are found to be overexpressed in cancers including colorectal, pancreatic, ovarian, and breast, with higher levels correlating to lower overall median survival. Although multiple lines of evidence suggest CtBP plays a role in tumorigenesis, it has never been formally characterized as …

Overcoming Treatment Resistance In Heterogeneous Tumors, Nikhil Hebbar

Theses and Dissertations--Toxicology and Cancer Biology

Most primary tumors are heterogeneous and are often composed of therapy-sensitive and emerging therapy-resistant cancer cells. Rather unexpectedly, treatment of therapy-sensitive tumor cells in heterogeneous tumor microenvironments resulted in apoptosis of the therapy-resistant cancer cells. We identified a novel Par-4 amino-terminal fragment (PAF, which includes amino acids 1-131 of Par-4) that is produced and released by therapy-sensitive cancer cells following therapy-induced caspase-dependent cleavage of the tumor suppressor Par-4. PAF caused paracrine apoptosis in therapy-resistant cancer cells. Unlike Par-4-inducible apoptosis, which is dependent on the cell surface GRP78 receptor, PAF produced cancer-selective apoptosis independent of cell surface GRP78 function. Par-4 contains …

Real-Time Detection Of Breast Cancer Cells Using Peptidefunctionalized Microcantilever Arrays, Hashem Etayash, Keren Jiang, Sarfuddin Azmi, Thomas Thundat, Kamaljit Kaur

Pharmacy Faculty Articles and Research

Ligand-directed targeting and capturing of cancer cells is a new approach for detecting circulating tumor cells (CTCs). Ligands such as antibodies have been successfully used for capturing cancer cells and an antibody based system (CellSearch®) is currently used clinically to enumerate CTCs. Here we report the use of a peptide moiety in conjunction with a microcantilever array system to selectively detect CTCs resulting from cancer, specifically breast cancer. A sensing microcantilever, functionalized with a breast cancer specific peptide 18-4 (WxEAAYQrFL), showed significant deflection on cancer cell (MCF7 and MDA-MB-231) binding compared to when exposed to noncancerous (MCF10A and HUVEC) cells. …

Targeting Il13ralpha2 Activates Stat6-Tp63 Pathway To Suppress Breast Cancer Lung Metastasis, Panagiotis Papageorgis, Sait Ozturk, Arthur W. Lambert, Christiana M. Neophytou, Alexandros Tzatsos, Chen K. Wong, Sam Thiagalingam, Andreas I. Constantinou

Anatomy and Regenerative Biology Faculty Publications

Introduction

Basal-like breast cancer (BLBC) is an aggressive subtype often characterized by distant metastasis, poor patient prognosis, and limited treatment options. Therefore, the discovery of alternative targets to restrain its metastatic potential is urgently needed. In this study, we aimed to identify novel genes that drive metastasis of BLBC and to elucidate the underlying mechanisms of action.

Methods

An unbiased approach using gene expression profiling of a BLBC progression model and in silicoleveraging of pre-existing tumor transcriptomes were used to uncover metastasis-promoting genes. Lentiviral-mediated knockdown of interleukin-13 receptor alpha 2 (IL13Ralpha2) coupled with whole-body in vivo bioluminescence imaging was …

Effect Of Sirna Pre-Exposure On Subsequent Response To Sirna Therapy, Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Cezary Kucharski, Nicole Chan, Hasan Uludag

Pharmacy Faculty Articles and Research

PURPOSE. An alternative cancer therapy based on RNA interference (RNAi) has shown considerable promise but the possibility of resistance development is not known. This study explored the possibility of therapeutic resistance against siRNA nanoparticles in human cancer cells. METHODS. Two approaches to siRNA treatment were undertaken using lipid-modified polyethylenimines, a single high concentration (shock) and repeated increasing concentrations (gradual). The targets were Mcl-1, RPS6KA5 and KSP in MDA-MB-435 cells. RESULTS. There was no evidence of resistance development in shock-treated cells, while the decrease in mRNA levels of targeted proteins was not as robust in naïve cells in gradual treatment. However, …

Klf4-Sqstm1/P62-Associated Prosurvival Autophagy Contributes To Carfilzomib Resistance In Multiple Myeloma Models., Irene Riz, Teresa S. Hawley, Robert G. Hawley

Anatomy and Regenerative Biology Faculty Publications

Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. Because of a high rate of immunoglobulin synthesis, the endoplasmic reticulum of MM cells is subjected to elevated basal levels of stress. Consequently, proteasome inhibitors, which exacerbate this stress by inhibiting ubiquitin-proteasome-mediated protein degradation, are an important new class of chemotherapeutic agents being used to combat this disease. However, MM cells still develop resistance to proteasome inhibitors such as carfilzomib. Toward this end, we have established carfilzomib-resistant derivatives of MM cell lines. We found that resistance to carfilzomib was associated with elevated levels of prosurvival autophagy, and Kruppel-like factor 4 …

Clinical Applications Of A Combination Chemotherapy Using 8-Chloro Camp And 8-Chloro Adenosine, Erik Munoz, Andrea Saich, Andrew Cox, Yu-An Peter Chang

Student Scholar Symposium Abstracts and Posters

Dr. Cho-Chung from the NIH first thought to use halogenated cAMP derivatives as competitive inhibitors of cAMP to slow down cancer cell mitosis. While the iodine and bromine substituted versions showed very little therapeutic actions, 8-Chloro cAMP has been shown to have strong anti-cancer effects. This has been shown in the phase II clinical trials this drug has undergone. However, these trials have had issues with solubility and toxicity. The drug is similar to vitamin C and is excreted quickly. Scientists tried to overcome this by using a peristaltic pump to give patients a continuous dosage, but this proved too …

Cancer Associated Fibroblast Derived Angiogenic Factor Mfap5 In Ovarian Cancer Progression, Sze Lee Cecilia Leung

Dissertations and Theses (Open Access)

Advanced stage ovarian cancer is the most lethal gynecologic malignancy. No major improvement on patient survival has been achieved in the past decade. Therefore, identification of predictive or prognostic markers and further understanding of the molecular mechanisms in ovarian cancer progression are of paramount importance.

While cancer cells have always been the targets for the identification of prognostic and predictive markers, the potential for developing new diagnosis and treatments based on the tumor supporting stromal microenvironment is relatively unexplored. Using transcriptome profiling analysis on microdissected stromal and epithelial components of normal and malignant ovarian tissues, we identified a gene signature …

Translation Initiation Complex Eif4f Is A Therapeutic Target For Dual Mtor Kinase Inhibitors In Non-Hodgkin Lymphoma., Christos Demosthenous, Jing Jing Han, Mary J Stenson, Matthew J Maurer, Linda E Wellik, Brian Link, Kristen Hege, Ahmet Dogan, Eduardo Sotomayor, Thomas Witzig, Mamta Gupta

Medicine Faculty Publications

Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor …

Image Enhancement Of Cancerous Tissue In Mammography Images, Richard Thomas Richardson

CCAC Theses and Dissertations

This research presents a framework for enhancing and analyzing time-sequenced mammographic images for detection of cancerous tissue, specifically designed to assist radiologists and physicians with the detection of breast cancer. By using computer aided diagnosis (CAD) systems as a tool to help in the detection of breast cancer in computed tomography (CT) mammography images, previous CT mammography images will enhance the interpretation of the next series of images. The first stage of this dissertation applies image subtraction to images from the same patient over time. Image types are defined as temporal subtraction, dual-energy subtraction, and Digital Database for Screening Mammography …

Targeting Cell Cycle Proteins In Breast Cancer Cells With Sirna By Using Lipid-Substituted Polyethylenimines, Manoj Parmar, Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Cezary Kucharski, Robert Maranchuk, Judith C. Hugh, Hasan Uludag

Pharmacy Faculty Articles and Research

The cell cycle proteins are key regulators of cell cycle progression whose de-regulation is one of the causes of breast cancer. RNA interference (RNAi) is an endogenous mechanism to regulate gene expression and it could serve as the basis of regulating aberrant proteins including cell cycle proteins. Since the delivery of small interfering RNA (siRNA) is a main barrier for implementation of RNAi therapy, we explored the potential of a non-viral delivery system, 2.0 kDa polyethylenimines substituted with linoleic acid and caprylic acid, for this purpose. Using a library of siRNAs against cell cycle proteins, we identified cell division cycle …

Clinical Significance Of A Point Mutation In Dna Polymerase Beta (Polb) Gene In Gastric Cancer., Xiaohui Tan, Hongyi Wang, Guangbin Luo, Shuyang Ren, Wenmei Li, Jiantao Cui, Harindarpal S. Gill, Sidney W. Fu, Youyong Lu

Medicine Faculty Publications

Gastric cancer (GC) is a major cause of global cancer mortality. Genetic variations in DNA repair genes can modulate DNA repair capability and, consequently, have been associated with risk of developing cancer. We have previously identified a T to C point mutation at nucleotide 889 (T889C) in DNA polymerase beta (POLB) gene, a key enzyme involved in base excision repair in primary GCs. The purpose of this study was to evaluate the mutation and expression of POLB in a larger cohort and to identify possible prognostic roles of the POLB alterations in GC. Primary GC specimens and their matched normal …

Ua94/6/15 Student / Alumni Personal Papers Wku Dorris Hutchinson, Wku Archives

WKU Archives Collection Inventories

Correspondence and publications created by and about the Dorris Hutchison during her time at Sloan-Kettering Institute.

May Circulating Micrornas Be Gastric Cancer Diagnostic Biomarkers?, Xiaoling Wu, Xiaohui (Jane) Tan, Sidney W. Fu

Medicine Faculty Publications

Gastric cancer (GC) is the third leading cause of cancer-related deaths. More than 80% of the diagnosis was made at the advanced stages of the disease, highlighting the urgent demand for novel biomarkers that can be used for early detection. Recently, a number of studies suggest that circulating microRNAs (miRNAs) could be potential biomarkers for GC diagnosis. Cancer-related circulating miRNAs, as well as tissue miRNAs, provide a hopeful prospect of detecting GC at early stages, and the prospective participation of miRNAs in biomarker development will enhance the sensitivity and specificity of diagnostic tests for GC. As miRNAs in blood are …

Engineered Plga Nanoparticles For Delivery Of Sirna In Mcf-7 Breast Cancer Cells, Sydney Pong, Samit Shah, Vivek Gupta

Student Scholar Symposium Abstracts and Posters

Small interfering RNAs have been an emerging medical treatment for molecular based diseases as they are capable of gene-specific knockdown. Appropriate and efficient delivery remains one of the biggest challenges in the development of siRNA as an anti-cancer treatment. Nanoparticles containing siRNA were characterized and the efficacy of various peptides in the transfection of the nanoparticles were tested. A gene silencing assay was developed in order to determine the effect of siRNA therapeutics on gene functionality in breast cancer cells.

Toxicity And Cosmesis Outcomes For Single Fraction Intra-Operative Electron Radiotherapy (Ioert) For Breast Cancer, Monica Hanna, Robert Ash, Wesley Babaran, Michele M. Carpenter, Afshin Forouzannia, Jay K. Harness, Brian Kaltenecker, Snehith Maddula, Venita Williams, Lawrence Wagman

Student Scholar Symposium Abstracts and Posters

Background: Adjuvant radiation therapy is proven to reduce local recurrence in patients with early stage breast cancer. To reduce toxicity, improve geographic accuracy, and reduce treatment time, IOERT can be utilized as an alternative to external beam radiation therapy. The study’s objective was to determine the short term toxicity and cosmesis profile of single fraction IOERT given as definitive treatment in a community setting. Materials and Methods: From Mar 2012 to Jul 2014, 84 patients (3 bilateral), ages 45-91 y.o. with stage 0-II were treated with IOERT (Mobetron, IntraOp Medical, Sunnyvale, CA). A single 21 Gy fraction was administered to …

Molecular Insights Into Prostate Field Cancerization: Telomere Length, Egr-­‐1 Expression, And Regulation Of Mic-­‐1, Pdgf-­‐A, And Fas, Emily Frisch, Kristin Gabriel, Marco Bisoffi

Student Scholar Symposium Abstracts and Posters

The diagnosis of prostate cancer (adenocarcinoma) relies on screening for elevated prostate-specific antigen (PSA) in blood samples and on digital rectal examination (DRE). With high PSA levels and/or abnormal DRE, physicians recommend a biopsy, which often misses the location of the adenocarcinoma and results in false negatives. Previous studies have shown expression of the key transcription factor early growth response 1 (EGR-1), the pro-survival factor macrophage inhibitor cytokine 1 (MIC-1), and the growth stimulatory platelet derived growth factor A (PDGF-A) to be up-regulated in histologically normal tissues 1 centimeter adjacent to prostate adenocarcinomas. We hypothesize that tumors emerge from “field …

The Role Of Ape/Ref-1 In Hepatocellular Carcinoma Progression, Zhen Yang, Sun Yang, Bobbye J. Misner, Feng Liu-Smith, Frank L. Meyskens

Pharmacy Faculty Articles and Research

Hepatocellular carcinoma (HCC) is responsible for a third of the estimated cancer-caused deaths worldwide. To deeply understand the mechanisms controlling HCC progression is of primary importance to develop new approaches for treatment. Apurinic/apyrimidinic endonuclease-1/redox effector factor 1 (APE/Ref-1) has been uncovered elevated in various types of cancer, including HCC. Additionally, HCC progression is always correlated with elevated copper (Cu). Our previous data demonstrated that Cu treatment initiated APE/Ref-1 expression and its downstream targets. Therefore, we hypothesized that APE/Ref-1 may be involved in HCC progression through mediating the effect of Cu to its signaling cascades. Following different treatments, human HCC cell …

Strategies To Sensitize Bladder Cancer Cells To Small Molecule Inhibitors Targeting The Pi3k Pathway, Giovanni Nitti

Dissertations and Theses (Open Access)

After many years of cancer research, it is well accepted by the scientific community that the future cure for this disease lies in a personalized therapeutic approach. Anticipating therapeutic outcome based on the genetic signature of a tumor has become the new paradigm. The PI3K pathway represents an ideal target for bladder cancer, as many of the key proteins of this pathway are altered or mutated in this particular type of cancer. Several small molecule inhibitors have been developed to target this pathway, but their efficacy has been shown to be heterogeneous among different cell lines and mostly cytostatic but …

Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer

University Scholar Projects

Somatic mutations may drive tumorigenesis or lead to new, immunogenic epitopes (neoantigens). The immune system is thought to represses neoplastic growths through the recognition of neoantigens presented only by tumor cells. To study mutations as well as the immune response to mutation-generated antigens, we have created a conditional knockin mouse line with a gene encoding, 5’ to 3’, yellow fluorescent protein (YFP), ovalbumin (which is processed to the immunologically recognizable peptide, SIINFEKL), and cyan fluorescent protein (CFP), or, YFP-ovalbumin-CFP. A frame shift mutation has been created at the 5’ end of the ovalbumin gene, hence YFP should always be expressed, …