Browsing by Subject "pancreatic ductal adenocarcinoma"

Now showing 1 - 8 of 8
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    Adapting AlphaLISA high throughput screen to discover a novel small-molecule inhibitor targeting protein arginine methyltransferase 5 in pancreatic and colorectal cancers
    (Impact Journals, 2017-05-23) Prabhu, Lakshmi; Wei, Han; Chen, Lan; Demir, Özlem; Sandusky, George; Sun, Emily; Wang, John; Mo, Jessica; Zeng, Lifan; Fishel, Melissa; Safa, Ahmad; Amaro, Rommie; Korc, Murray; Zhang, Zhong-Yin; Lu, Tao; Pharmacology and Toxicology, School of Medicine
    Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are notoriously challenging for treatment. Hyperactive nuclear factor κB (NF-κB) is a common culprit in both cancers. Previously, we discovered that protein arginine methyltransferase 5 (PRMT5) methylated and activated NF-κB. Here, we show that PRMT5 is highly expressed in PDAC and CRC. Overexpression of PRMT5 promoted cancer progression, while shRNA knockdown showed an opposite effect. Using an innovative AlphaLISA high throughput screen, we discovered a lead compound, PR5-LL-CM01, which exhibited robust tumor inhibition effects in both cancers. An in silico structure prediction suggested that PR5-LL-CM01 inhibits PRMT5 by binding with its active pocket. Importantly, PR5-LL-CM01 showed higher anti-tumor efficacy than the commercial PRMT5 inhibitor, EPZ015666, in both PDAC and CRC. This study clearly highlights the significant potential of PRMT5 as a therapeutic target in PDAC and CRC, and establishes PR5-LL-CM01 as a promising basis for new drug development in the future.
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    APE1/Ref-1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single-cell RNA sequencing
    (Wiley, 2017-12) Shah, Fenil; Goossens, Emery; Atallah, Nadia M.; Grimard, Michelle; Kelley, Mark R.; Fishel, Melissa L.; Department of Pediatrics, School of Medicine
    Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1 or APE1) is a multifunctional protein that regulates numerous transcription factors associated with cancer-related pathways. Because APE1 is essential for cell viability, generation of APE1-knockout cell lines and determining a comprehensive list of genes regulated by APE1 has not been possible. To circumvent this challenge, we utilized single-cell RNA sequencing to identify differentially expressed genes (DEGs) in relation to APE1 protein levels within the cell. Using a straightforward yet novel statistical design, we identified 2837 genes whose expression is significantly changed following APE1 knockdown. Using this gene expression profile, we identified multiple new pathways not previously linked to APE1, including the EIF2 signaling and mechanistic target of Rapamycin pathways and a number of mitochondrial-related pathways. We demonstrate that APE1 has an effect on modifying gene expression up to a threshold of APE1 expression, demonstrating that it is not necessary to completely knockout APE1 in cells to accurately study APE1 function. We validated the findings using a selection of the DEGs along with siRNA knockdown and qRT-PCR. Testing additional patient-derived pancreatic cancer cells reveals particular genes (ITGA1, TNFAIP2, COMMD7, RAB3D) that respond to APE1 knockdown similarly across all the cell lines. Furthermore, we verified that the redox function of APE1 was responsible for driving gene expression of mitochondrial genes such as PRDX5 and genes that are important for proliferation such as SIPA1 and RAB3D by treating with APE1 redox-specific inhibitor, APX3330. Our study identifies several novel genes and pathways affected by APE1, as well as tumor subtype specificity. These findings will allow for hypothesis-driven approaches to generate combination therapies using, for example, APE1 inhibitor APX3330 with other approved FDA drugs in an innovative manner for pancreatic and other cancer treatments.
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    Biomimetic and enzyme-responsive dynamic hydrogels for studying cell-matrix interactions in pancreatic ductal adenocarcinoma
    (Elsevier, 2018-04) Liu, Hung-Yi; Korc, Murray; Lin, Chien-Chi; Biomedical and Applied Sciences, School of Dentistry
    The tumor microenvironment (TME) governs all aspects of cancer progression and in vitro 3D cell culture platforms are increasingly developed to emulate the interactions between components of the stromal tissues and cancer cells. However, conventional cell culture platforms are inadequate in recapitulating the TME, which has complex compositions and dynamically changing matrix mechanics. In this study, we developed a dynamic gelatin-hyaluronic acid hybrid hydrogel system through integrating modular thiol-norbornene photopolymerization and enzyme-triggered on-demand matrix stiffening. In particular, gelatin was dually modified with norbornene and 4-hydroxyphenylacetic acid to render this bioactive protein photo-crosslinkable (through thiol-norbornene gelation) and responsive to tyrosinase-triggered on-demand stiffening (through HPA dimerization). In addition to the modified gelatin that provides basic cell adhesive motifs and protease cleavable sequences, hyaluronic acid (HA), an essential tumor matrix, was modularly and covalently incorporated into the cell-laden gel network. We systematically characterized macromer modification, gel crosslinking, as well as enzyme-triggered stiffening and degradation. We also evaluated the influence of matrix composition and dynamic stiffening on pancreatic ductal adenocarcinoma (PDAC) cell fate in 3D. We found that either HA-containing matrix or a dynamically stiffened microenvironment inhibited PDAC cell growth. Interestingly, these two factors synergistically induced cell phenotypic changes that resembled cell migration and/or invasion in 3D. Additional mRNA expression array analyses revealed changes unique to the presence of HA, to a stiffened microenvironment, or to the combination of both. Finally, we presented immunostaining and mRNA expression data to demonstrate that these irregular PDAC cell phenotypes were a result of matrix-induced epithelial-mesenchymal transition (EMT).
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    Cancer History: A Predictor of IPMN Subtype and Dysplastic Status?
    (Elsevier, 2017) Carr, Rosalie A.; Kiel, Brandon A.; Roch, Alexandra M.; Ceppa, Eugene P.; House, Michael G.; Zyromski, Nicholas J.; Nakeeb, Attila; Schmidt, C. Max; Surgery, School of Medicine
    Introduction The aim of this study was to determine the association of PMH and FH of pancreatic (PDAC) and non-pancreatic cancers with IPMN malignant risk. Methods A retrospective review of a prospective database of IPMN patients undergoing resection was performed to assess FH and PMH. Results FH of PDAC was present in 13% of 362 included patients. Of these, 8% had at least one first degree relative (FDR) with PDAC. The rate of PDAC positive FH in non-invasive versus invasive IPMN patients was 14% and 8%, respectively (p = 0.3). In main duct IPMN patients, FH (44%) and PMH of non-pancreatic cancer (16%) was higher than that seen in branch duct IPMN (FH 29%; PMH 6%; p = 0.004 and 0.008). Conclusions FH of PDAC is not associated with IPMN malignant progression. FH and PMH of non-pancreatic cancer is associated with main duct IPMN, the subtype with the highest rate of invasive transformation.
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    Designer hydrogels: Shedding light on the physical chemistry of the pancreatic cancer microenvironment
    (Elsevier, 2018-11) Lin, Chien-Chi; Korc, Murray; Biomedical Engineering, School of Engineering and Technology
    Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer mortality in the United States, with a 5-year survival of ∼8%. PDAC is characterized by a dense and hypo-vascularized stroma consisting of proliferating cancer cells, cancer-associated fibroblasts, macrophages and immune cells, as well as excess matrices including collagens, fibronectin, and hyaluronic acid. In addition, PDAC has increased interstitial pressures and a hypoxic/acidic tumor microenvironment (TME) that impedes drug delivery and blocks cancer-directed immune mechanisms. In spite of increasing options in targeted therapy, PDAC has mostly remained treatment recalcitrant. Owing to its critical roles on governing PDAC progression and treatment outcome, TME and its interplay with the cancer cells are increasingly studied. In particular, three-dimensional (3D) hydrogels derived from or inspired by components in the TME are progressively developed. When properly designed, these hydrogels (e.g., Matrigel, collagen gel, hyaluronic acid-based, and semi-synthetic hydrogels) can provide pathophysiologically relevant compositions, conditions, and contexts for supporting PDAC cell fate processes. This review summarizes recent efforts in using 3D hydrogels for fundamental studies on cell-matrix or cell-cell interactions in PDAC.
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    Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer
    (ACS, 2019) Shouksmith, Andrew E.; Shah, Fenil; Grimard, Michelle L.; Gawel, Justyna M.; Raouf, Yasir; Geletu, Mulu; Berger-Becvar, Angelika; de Araujo, Elvin D.; Luchman, H. Artee; Heaton, William L.; Bakhshinyan, David; Adile, Ashley A.; Venugopal, Chitra; O'Hare, Thomas; Deininger, Michael W.; Singh, Sheila K.; Konieczny, Stephen F.; Weiss, Samuel; Fishel, Melissa L.; Gunning, Patrick T.; Pediatrics, School of Medicine
    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% 1 year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments, and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC. We developed an inhibitor of HDACs, AES-135, that exhibits nanomolar inhibitory activity against HDAC3, HDAC6, and HDAC11 in biochemical assays. In a three-dimensional coculture model, AES-135 kills low-passage patient-derived tumor spheroids selectively over surrounding cancer-associated fibroblasts and has excellent pharmacokinetic properties in vivo. In an orthotopic murine model of pancreatic cancer, AES-135 prolongs survival significantly, therefore representing a candidate for further preclinical testing.
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    A Multidisciplinary Approach to Pancreas Cancer in 2016: A Review
    (Nature, 2017) Fogel, Evan L.; Shahda, Safi; Sandrasegaran, Kumar; DeWitt, John; Easler, Jeffrey J.; Agarwal, David M.; Eagleson, Mackenzie; Zyromski, Nicholas J.; House, Michael G.; Ellsworth, Susannah; El Hajj, Ihab I.; O'Neil, Bert H.; Nakeeb, Attila; Sherman, Stuart; Medicine, School of Medicine
    In this article, we review our multidisciplinary approach for patients with pancreatic cancer. Specifically, we review the epidemiology, diagnosis and staging, biliary drainage techniques, selection of patients for surgery, chemotherapy, radiation therapy, and discuss other palliative interventions. The areas of active research investigation and where our knowledge is limited are emphasized.
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    Pancreatic Cancer Center: Providing the Research Tools Necessary to Advance Pancreatic Cancer Patient Care
    (Office of the Vice Chancellor for Research, 2013-04-05) Korc, Murray; Kelley, Mark R.
    There were approximately 43,000 new cases of pancreatic ductal adenocarcinoma (PDAC) in the U.S. in 2010, and approximately 37,000 deaths. PDAC thus constitutes the fourth leading cause of cancer deaths, and PDAC patients have a dismal 5-year survival rate of 6%; approximately 75% of patients die within the first year after diagnosis. PDAC is notoriously resistant to chemotherapy and radiation and even with our best treatment options, a complete margin-negative surgical resection, few patients achieve long-term survival. Despite these statistics, surprisingly only a small number of NCI-designated cancer centers have a specialized pancreatic cancer program. The creation of the IUPUI Signature Center for Pancreatic Cancer Research has been the foundation for putting IUPUI, the IU School of Medicine, Purdue University and the IU Simon Cancer Center at the forefront of pancreatic cancer treatment and research across the nation. The Signature Center, comprised of basic, translational and clinical researchers, represents the continuum of the disease from biological / molecular investigation to clinical trials. Funding from the Signature Center Initiative is being utilized to develop genetically engineered mouse models, generate orthotopic pancreatic cancer mouse models as well as provide funding for peer reviewed pilot projects. Establishment and characterization of these in vivo models provides the groundwork to be used by all members in their translational research projects; support of pilot projects provides preliminary data and identification of projects to be used in a SPORE application. Additionally, work has begun on a web portal to promote and educate both patients and clinicians about the IUSCC Pancreas Cancer Clinic which became operational in 2010. Taken together these activities provide the infrastructure to support pancreas cancer research at IU across the continuum of bench to bedside to practice. The availability of these resources to all members promotes inter-disciplinary collaborations aimed at increasing our understanding of pancreatic cancer so that advancements can be made in diagnosis, prevention and treatment of this malignancy.