During the last grant period, we have obtained evidence that the expression of connective tissue growth factor (CTGF) is elevated in human pancreatic tumors, but not in normal pancreas or pancreatitis. Since pancreatic tumors are highly hypoxia and CTGF is known to be hypoxia inducible, we have focused this grant to understand the role of hypoxia and CTGF in pancreatic tumor progression. The basis for these studies to investigate the importance of CTGF in pancreatic tumor progression derive from our demonstration that targeted inhibition of CTGF with a monoclonal specific antibody results in significant growth inhibition of two different pancreatic cancer cell lines implanted as subcutaneous tumors. In this competitive renewal, Project 1 will focus on determining the mechanistic role of CTGF and its individual domains on pancreatic tumor progression under normoxic and hypoxic conditions. Our preliminary data suggests that CTGF is able to enhance the growth of pancreatic tumor cells. Induction of CTGF had no effect on cell growth on plastic, but significantly enhanced spheroid growth in soft agar. Most striking was the increase in cell adhesion induced by CTGF expression. These changes in cell adhesion that are necessary for 3-D growth lead us to test the hypothesis that one of the major roles of CTGF in malignant progression is to regulate cell-cell adhesion, and that inhibiting this activity will impact tumor growth and metastases. Thus, the aims of this proposal are to 1) determine how CTGF affects cell adhesion of pancreatic tumor cells under normoxic and hypoxic conditions using domain specific deletion mutants in cells that are manipulated to express different levels of HIF-1 (Project 3), 2) determine how important CTGF is for 3-D growth and invasion under normoxic and hypoxic conditions, 3) determine how inhibition of CTGF mediated adhesion affects metastatic growth, 4) determine how inhibition of cell adhesion by CTGF affects subcutaneous and orthotopic tumor growth of pancreatic tumor cells and in collaboration with Project 4 head and neck tumors, 5) determine the role of stromal and tumor cell CTGF on tumor growth, 6) determine how effective the combination of CTGF Ab and the new hypoxic specific cytotoxin PR-104 are in controlling pancreatic tumor growth compared to CTGF Ab and gemcitabine (Project 2). In summary, the proposed studies are intended to address an important mechanism by which CTGF affects tumor progression in pancreatic cancers and to determine how effective it is in combination therapy to bring it to the clinic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA067166-15S1
Application #
8492949
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
2011-02-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
15
Fiscal Year
2012
Total Cost
$118,350
Indirect Cost
$43,789
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Bobko, Andrey A; Evans, Jason; Denko, Nicholas C et al. (2016) Concurrent Longitudinal EPR Monitoring of Tissue Oxygenation, Acidosis, and Reducing Capacity in Mouse Xenograft Tumor Models. Cell Biochem Biophys :
Zeidan, Youssef H; Xiao, Nan; Cao, Hongbin et al. (2016) Botulinum Toxin Confers Radioprotection in Murine Salivary Glands. Int J Radiat Oncol Biol Phys 94:1190-7
Jiang, Dadi; Lynch, Connor; Medeiros, Bruno C et al. (2016) Identification of Doxorubicin as an Inhibitor of the IRE1α-XBP1 Axis of the Unfolded Protein Response. Sci Rep 6:33353
Vilalta, Marta; Rafat, Marjan; Graves, Edward E (2016) Effects of radiation on metastasis and tumor cell migration. Cell Mol Life Sci 73:2999-3007
Rankin, Erinn B; Giaccia, Amato J (2016) Hypoxic control of metastasis. Science 352:175-80
Sun, Ramon C; Koong, Albert; Giaccia, Amato et al. (2016) Measuring the Impact of Microenvironmental Conditions on Mitochondrial Dehydrogenase Activity in Cultured Cells. Adv Exp Med Biol 899:113-20
Leszczynska, Katarzyna B; Göttgens, Eva-Leonne; Biasoli, Deborah et al. (2016) Mechanisms and consequences of ATMIN repression in hypoxic conditions: roles for p53 and HIF-1. Sci Rep 6:21698
Olcina, Monica M; Giaccia, Amato J (2016) Reducing radiation-induced gastrointestinal toxicity - the role of the PHD/HIF axis. J Clin Invest 126:3708-3715
Alagappan, Muthuraman; Jiang, Dadi; Denko, Nicholas et al. (2016) A Multimodal Data Analysis Approach for Targeted Drug Discovery Involving Topological Data Analysis (TDA). Adv Exp Med Biol 899:253-68
LaGory, Edward L; Giaccia, Amato J (2016) The ever-expanding role of HIF in tumour and stromal biology. Nat Cell Biol 18:356-65

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