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Pancreatic Neoplasms: HELP
Articles by George E. Sandusky
Based on 8 articles published since 2010
(Why 8 articles?)
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Between 2010 and 2020, George Sandusky wrote the following 8 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy. 2019

Zhong, Xiaoling / Pons, Marianne / Poirier, Christophe / Jiang, Yanlin / Liu, Jianguo / Sandusky, George E / Shahda, Safi / Nakeeb, Attila / Schmidt, C Max / House, Michael G / Ceppa, Eugene P / Zyromski, Nicholas J / Liu, Yunlong / Jiang, Guanglong / Couch, Marion E / Koniaris, Leonidas G / Zimmers, Teresa A. ·Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA. · IUPUI Center for Cachexia Innovation, Research and Therapy, Indianapolis, IN, USA. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. · IU Simon Cancer Center, Indianapolis, IN, USA. · Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. · Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA. · Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Otolaryngology-Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. ·J Cachexia Sarcopenia Muscle · Pubmed #31286691.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice. METHODS: Isoform-specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed-forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes. RESULTS: Murine PDAC tumour-derived cell lines expressed activin-βA but not activin-βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin-low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin-high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin-βA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not. CONCLUSIONS: Pancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ-specific and gene-specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle-specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene-specific and organ-specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling.

2 Article Blocking HIF signaling via novel inhibitors of CA9 and APE1/Ref-1 dramatically affects pancreatic cancer cell survival. 2018

Logsdon, Derek P / Shah, Fenil / Carta, Fabrizio / Supuran, Claudiu T / Kamocka, Malgorzata / Jacobsen, Max H / Sandusky, George E / Kelley, Mark R / Fishel, Melissa L. ·Indiana University School of Medicine, Department of Pharmacology and Toxicology, Indianapolis, IN, USA. · Indiana University School of Medicine, Department of Pediatrics, Wells Center for Pediatric Research, Indianapolis, IN, USA. · University of Florence, Neurofarba Department, Section of Medicinal Chemistry, Florence, Italy. · Indiana University School of Medicine, Department of Nephrology, Indianapolis, IN, USA. · Indiana University School of Medicine, Department of Pathology and Laboratory Medicine, Indianapolis, IN, USA. · Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, Indianapolis, IN, USA. · Indiana University School of Medicine, Department of Pharmacology and Toxicology, Indianapolis, IN, USA. mfishel@iu.edu. · Indiana University School of Medicine, Department of Pediatrics, Wells Center for Pediatric Research, Indianapolis, IN, USA. mfishel@iu.edu. ·Sci Rep · Pubmed #30214007.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has reactive stroma that promotes tumor signaling, fibrosis, inflammation, and hypoxia, which activates HIF-1α to increase tumor cell metastasis and therapeutic resistance. Carbonic anhydrase IX (CA9) stabilizes intracellular pH following induction by HIF-1α. Redox effector factor-1 (APE1/Ref-1) is a multifunctional protein with redox signaling activity that converts certain oxidized transcription factors to a reduced state, enabling them to upregulate tumor-promoting genes. Our studies evaluate PDAC hypoxia responses and APE1/Ref-1 redox signaling contributions to HIF-1α-mediated CA9 transcription. Our previous studies implicated this pathway in PDAC cell survival under hypoxia. We expand those studies, comparing drug responses using patient-derived PDAC cells displaying differential hypoxic responses in 3D spheroid tumor-stroma models to characterize second generation APE1/Ref-1 redox signaling and CA9 inhibitors. Our data demonstrates that HIF-1α-mediated CA9 induction differs between patient-derived PDAC cells and that APE1/Ref-1 redox inhibition attenuates this induction by decreasing hypoxia-induced HIF-1 DNA binding. Dual-targeting of APE1/Ref-1 and CA9 in 3D spheroids demonstrated that this combination effectively kills PDAC tumor cells displaying drastically different levels of CA9. New APE1/Ref-1 and CA9 inhibitors were significantly more potent alone and in combination, highlighting the potential of combination therapy targeting the APE1-Ref-1 signaling axis with significant clinical potential.

3 Article Safety and Efficacy of AAV Retrograde Pancreatic Ductal Gene Delivery in Normal and Pancreatic Cancer Mice. 2018

Quirin, Kayla A / Kwon, Jason J / Alioufi, Arafat / Factora, Tricia / Temm, Constance J / Jacobsen, Max / Sandusky, George E / Shontz, Kim / Chicoine, Louis G / Clark, K Reed / Mendell, Joshua T / Korc, Murray / Kota, Janaiah. ·Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, USA. · Department of Pathology, IUSM, Indianapolis, IN 46202, USA. · Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA. · Dimension Therapeutics, Cambridge, MA 02139, USA. · Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, IN 46202, USA. · Pancreatic Cancer Signature Center, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN 46202, USA. · Department of Biochemistry and Molecular Biology, IUSM, Indianapolis, IN 43202, USA. · Department of Medicine, IUSM, Indianapolis, IN 43202, USA. ·Mol Ther Methods Clin Dev · Pubmed #29349096.

ABSTRACT: Recombinant adeno-associated virus (rAAV)-mediated gene delivery shows promise to transduce the pancreas, but safety/efficacy in a neoplastic context is not well established. To identify an ideal AAV serotype, route, and vector dose and assess safety, we have investigated the use of three AAV serotypes (6, 8, and 9) expressing GFP in a self-complementary (sc) AAV vector under an EF1α promoter (scAAV.GFP) following systemic or retrograde pancreatic intraductal delivery. Systemic delivery of scAAV9.GFP transduced the pancreas with high efficiency, but gene expression did not exceed >45% with the highest dose, 5 × 10

4 Article Adapting AlphaLISA high throughput screen to discover a novel small-molecule inhibitor targeting protein arginine methyltransferase 5 in pancreatic and colorectal cancers. 2017

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. ·Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA. · Chemical Genomics Core Facility, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA. · Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. ·Oncotarget · Pubmed #28591716.

ABSTRACT: 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.

5 Article The Aurora-A-Twist1 axis promotes highly aggressive phenotypes in pancreatic carcinoma. 2017

Wang, Jing / Nikhil, Kumar / Viccaro, Keith / Chang, Lei / Jacobsen, Max / Sandusky, George / Shah, Kavita. ·Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN 47907, USA. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, room A-128, Indianapolis, IN 46202, USA. · Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN 47907, USA shah23@purdue.edu. ·J Cell Sci · Pubmed #28167680.

ABSTRACT: We uncovered a crucial role for the Aurora kinase A (AURKA)-Twist1 axis in promoting epithelial-to-mesenchymal transition (EMT) and chemoresistance in pancreatic cancer. Twist1 is the first EMT-specific target of AURKA that was identified using an innovative screen. AURKA phosphorylates Twist1 at three sites, which results in its multifaceted regulation - AURKA inhibits its ubiquitylation, increases its transcriptional activity and favors its homodimerization. Twist1 reciprocates and prevents AURKA degradation, thereby triggering a feedback loop. Ablation of either AURKA or Twist1 completely inhibits EMT, highlighting both proteins as central players in EMT progression. Phosphorylation-dead Twist1 serves as a dominant-negative and fully reverses the EMT phenotype induced by Twist1, underscoring the crucial role of AURKA-mediated phosphorylation in mediating Twist1-induced malignancy. Likewise, Twist1-overexpressing BxPC3 cells formed large tumors

6 Article Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics. 2016

Arpin, Carolyn C / Mac, Stephen / Jiang, Yanlin / Cheng, Huiwen / Grimard, Michelle / Page, Brent D G / Kamocka, Malgorzata M / Haftchenary, Sina / Su, Han / Ball, Daniel P / Rosa, David A / Lai, Ping-Shan / Gómez-Biagi, Rodolfo F / Ali, Ahmed M / Rana, Rahul / Hanenberg, Helmut / Kerman, Kagan / McElyea, Kyle C / Sandusky, George E / Gunning, Patrick T / Fishel, Melissa L. ·Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada. · Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana. · Department of Medicine, Division of Nephrology, Indiana Center for Biological Microscopy, Indiana University School of Medicine, Indianapolis, Indiana. · Department of Physical and Environmental Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada. · Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada. Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt. · Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana. Department of Pediatrics III, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany. Department of Otorhinolaryngology and Head/Neck Surgery (ENT), Heinrich Heine University, Dusseldorf, Germany. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana. · Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada. mfishel@iu.edu patrick.gunning@utoronto.ca. · Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana. Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana. mfishel@iu.edu patrick.gunning@utoronto.ca. ·Mol Cancer Ther · Pubmed #26873728.

ABSTRACT: Constitutively activated STAT3 protein has been found to be a key regulator of pancreatic cancer and a target for molecular therapeutic intervention. In this study, PG-S3-001, a small molecule derived from the SH-4-54 class of STAT3 inhibitors, was found to inhibit patient-derived pancreatic cancer cell proliferation in vitro and in vivo in the low micromolar range. PG-S3-001 binds the STAT3 protein potently, Kd = 324 nmol/L by surface plasmon resonance, and showed no effect in a kinome screen (>100 cancer-relevant kinases). In vitro studies demonstrated potent cell killing as well as inhibition of STAT3 activation in pancreatic cancer cells. To better model the tumor and its microenvironment, we utilized three-dimensional (3D) cultures of patient-derived pancreatic cancer cells in the absence and presence of cancer-associated fibroblasts (CAF). In this coculture model, inhibition of tumor growth is maintained following STAT3 inhibition in the presence of CAFs. Confocal microscopy was used to verify tumor cell death following treatment of 3D cocultures with PG-S3-001. The 3D model was predictive of in vivo efficacy as significant tumor growth inhibition was observed upon administration of PG-S3-001. These studies showed that the inhibition of STAT3 was able to impact the survival of tumor cells in a relevant 3D model, as well as in a xenograft model using patient-derived cells. Mol Cancer Ther; 15(5); 794-805. ©2016 AACR.

7 Article Pachymic acid inhibits growth and induces apoptosis of pancreatic cancer in vitro and in vivo by targeting ER stress. 2015

Cheng, Shujie / Swanson, Kristen / Eliaz, Isaac / McClintick, Jeanette N / Sandusky, George E / Sliva, Daniel. ·Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America. · Amitabha Medical Clinic and Healing Center, Santa Rosa, California, United States of America. · Departments of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, Indiana, United States of America. · Departments of Pathology, School of Medicine, Indiana University, Indianapolis, Indiana, United States of America. · Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America; Departments of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, United States of America; DSTest Laboratories, Purdue Research Park, Indianapolis, Indiana, United States of America. ·PLoS One · Pubmed #25915041.

ABSTRACT: Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos. In this paper, we investigated the anticancer effect of PA on human chemotherapy resistant pancreatic cancer. PA triggered apoptosis in gemcitabine-resistant pancreatic cancer cells PANC-1 and MIA PaCa-2. Comparative gene expression array analysis demonstrated that endoplasmic reticulum (ER) stress was induced by PA through activation of heat shock response and unfolded protein response related genes. Induced ER stress was confirmed by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and phospho-eIF2α. Moreover, ER stress inhibitor tauroursodeoxycholic acid (TUDCA) blocked PA induced apoptosis. In addition, 25 mg kg-1 of PA significantly suppressed MIA PaCa-2 tumor growth in vivo without toxicity, which correlated with induction of apoptosis and expression of ER stress related proteins in tumor tissues. Taken together, growth inhibition and induction of apoptosis by PA in gemcitabine-resistant pancreatic cancer cells were associated with ER stress activation both in vitro and in vivo. PA may be potentially exploited for the use in treatment of chemotherapy resistant pancreatic cancer.

8 Article Reduced expression of DNA repair and redox signaling protein APE1/Ref-1 impairs human pancreatic cancer cell survival, proliferation, and cell cycle progression. 2010

Jiang, Yanlin / Zhou, Shaoyu / Sandusky, George E / Kelley, Mark R / Fishel, Melissa L. ·Department of Pediatrics, Herman B Wells Center for Pediatric Research, Walnut, Indianapolis 46202, USA. ·Cancer Invest · Pubmed #20919954.

ABSTRACT: Pancreatic cancer is a deadly disease that is virtually never cured. Understanding the chemoresistance intrinsic to this cancer will aid in developing new regimens. High expression of APE1/Ref-1, a DNA repair and redox signaling protein, is associated with resistance, poor outcome, and angiogenesis; little is known in pancreatic cancer. Immunostaining of adenocarcinoma shows greater APE1/Ref-1 expression than in normal pancreas tissue. A decrease in APE1/Ref-1 protein levels results in pancreatic cancer cell growth inhibition, increased apoptosis, and altered cell cycle progression. Endogenous cell cycle inhibitors increase when APE1/ Ref-1 is reduced, demonstrating its importance to proliferation and growth of pancreatic cancer.