Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Pancreatic Neoplasms: HELP
Articles by James T. Topham
Based on 2 articles published since 2010
(Why 2 articles?)
||||

Between 2010 and 2020, James T. Topham wrote the following 2 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia. 2019

McDonald, Paul C / Chafe, Shawn C / Brown, Wells S / Saberi, Saeed / Swayampakula, Mridula / Venkateswaran, Geetha / Nemirovsky, Oksana / Gillespie, Jordan A / Karasinska, Joanna M / Kalloger, Steve E / Supuran, Claudiu T / Schaeffer, David F / Bashashati, Ali / Shah, Sohrab P / Topham, James T / Yapp, Donald T / Li, Jinyang / Renouf, Daniel J / Stanger, Ben Z / Dedhar, Shoukat. ·Department of Integrative Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada. · Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada. · Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada. · NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Sesto Fiorentino, Florence, Italy. · Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada. · Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. · Medical Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada. · Department of Integrative Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada. Electronic address: sdedhar@bccrc.ca. ·Gastroenterology · Pubmed #31078621.

ABSTRACT: BACKGROUND & AIMS: Most pancreatic ductal adenocarcinomas (PDACs) express an activated form of KRAS, become hypoxic and dysplastic, and are refractory to chemo and radiation therapies. To survive in the hypoxic environment, PDAC cells upregulate enzymes and transporters involved in pH regulation, including the extracellular facing carbonic anhydrase 9 (CA9). We evaluated the effect of blocking CA9, in combination with administration of gemcitabine, in mouse models of pancreatic cancer. METHODS: We knocked down expression of KRAS in human (PK-8 and PK-1) PDAC cells with small hairpin RNAs. Human and mouse (Kras RESULTS: Under hypoxic conditions, PDAC cells had increased levels of HIF1A and HIF2A, upregulated expression of CA9, and activated glycolysis. Knockdown of KRAS in PDAC cells, or incubation with trametinib, reduced the posttranscriptional stabilization of HIF1A and HIF2A, upregulation of CA9, pHi, and glycolysis in response to hypoxia. CA9 was expressed by 66% of PDAC samples analyzed; high expression of genes associated with metabolic adaptation to hypoxia, including CA9, correlated with significantly reduced survival times of patients. Knockdown or pharmacologic inhibition of CA9 in PDAC cells significantly reduced pHi in cells under hypoxic conditions, decreased gemcitabine-induced glycolysis, and increased their sensitivity to gemcitabine. PDAC cells with knockdown of CA9 formed smaller xenograft tumors in mice, and injection of gemcitabine inhibited tumor growth and significantly increased survival times of mice. In mice with xenograft tumors grown from human PDAC cells, oral administration of SLC-0111 and injection of gemcitabine increased intratumor acidosis and increased cell death. These tumors, and tumors grown from PDAC patient-derived tumor fragments, grew more slowly than xenograft tumors in mice given control agents, resulting in longer survival times. In Kras CONCLUSIONS: In response to hypoxia, PDAC cells that express activated KRAS increase expression of CA9, via stabilization of HIF1A and HIF2A, to regulate pH and glycolysis. Disruption of this pathway slows growth of PDAC xenograft tumors in mice and might be developed for treatment of pancreatic cancer.

2 Article None 2019

Jones, Martin R / Williamson, Laura M / Topham, James T / Lee, Michael K C / Goytain, Angela / Ho, Julie / Denroche, Robert E / Jang, GunHo / Pleasance, Erin / Shen, Yaoquing / Karasinska, Joanna M / McGhie, John P / Gill, Sharlene / Lim, Howard J / Moore, Malcolm J / Wong, Hui-Li / Ng, Tony / Yip, Stephen / Zhang, Wei / Sadeghi, Sara / Reisle, Carolyn / Mungall, Andrew J / Mungall, Karen L / Moore, Richard A / Ma, Yussanne / Knox, Jennifer J / Gallinger, Steven / Laskin, Janessa / Marra, Marco A / Schaeffer, David F / Jones, Steven J M / Renouf, Daniel J. ·BC Cancer, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada. · Pancreas Centre British Columbia, Vancouver, Canada. · BC Cancer, Division of Medical Oncology, Vancouver, British Columbia, Canada. · Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, British Columbia, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, British Columbia, Canada. · Pancreas Centre British Columbia, Vancouver, Canada. drenouf@bccancer.bc.ca. ·Clin Cancer Res · Pubmed #31068372.

ABSTRACT: PURPOSE: Gene fusions involving neuregulin 1 ( EXPERIMENTAL DESIGN: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving RESULTS: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as CONCLUSIONS: This work adds to a growing body of evidence that