Epidermal growth factor receptor (EGF-R) regulates the growth and progression of human pancreatic carcinoma. Both angiogenesis and EGF-R signaling mechanisms are fundamental to the progression of human pancreatic carcinoma, but the link between the two processes has only recently been identified. We observed the regression of established pancreatic carcinoma growing in the pancreas of nude mice following in vivo EGF-R blockade, which could not be explained by the modest in vitro 30% cytostatic effect. This response is mediated, in part, by inhibition of angiogenesis and is independent of antiproliferation. VEGF and IL-8 (but not bFGF) expression was significantly lower in treated tumors than in controls. The down regulation of these angiogenic factors preceded the involution of blood vessels as shown directly by double label immunofluorescence of apoptotic endothelial and tumor cells. Preliminary analyses using VEGF - R (murine Flk -I) blockade therapy further implicate VEGF as an important regulator of this process. These studies indicate that therapies inhibiting EGF-R signaling have a significant antitumor effect mediated, in part, by inhibition of angiogenesis. The purpose of this proposal is to develop and validate specific surrogate markers of EGF-R directed therapy in combination with gemcitabine in a preclinical model and extend this information to pancreatic carcinoma specimens before and after EGF-R blockade therapy in combination with gemcitabine in a Phase II clinical trial.
Three specific aims will be pursued. First, we will establish a panel of surrogate markers for the anti-angiogenic effects of EGF- R blockade alone and in combination with gemcitabine. Tumor cell-specific and serum levels of distinct angiogenic factors will be correlated with microvessel density, endothelial cell-specific markers, rates of endothelial cell apoptosis, imaging of microvessel permeability and blood flow, and ultimately with tumor cell apoptosis in an orthotopic pancreatic carcinoma animal model. Alternative strategies of EGF -R blockade including EGF-R selective tyrosine kinase inhibitors will be utilized to verify that the effect is specific to EGF-R blockade and not the individual type of inhibitor. Second, we will develop and validate a panel of surrogate markers for the effects of EGF-R blockade therapy alone and in combination with gemcitabine on specific components of the EGF -R signaling pathway which are involved regulating angiogenic factor production in tumor cells growing in vitro and in nude mice. Finally, we will validate and correlate the surrogate markers developed preclinically With clinical staging, response to therapy, and outcome in pancreatic carcinoma patients treated with EGF -R blockade therapy in combination with gemcitabine in a phase II clinical trial (DM99-147). The knowledge gained from this research will allow the identification of biologically relevant biomarkers of EGF-R targeted therapies and assess if distinct surrogate markers can be validated to predict not only a molecular target-specific response, but a tumoricidal response mediated, in part, by inhibition of angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA090810-02
Application #
6563958
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2002-01-01
Project End
2002-12-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
2
Fiscal Year
2002
Total Cost
$296,752
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Wang, Ruoning; Jung, Sung Yun; Wu, Chuan Fen et al. (2010) Direct roles of the signaling kinase RSK2 in Cdc25C activation during Xenopus oocyte maturation. Proc Natl Acad Sci U S A 107:19885-90
Kopetz, Scott; Hoff, Paulo M; Morris, Jeffrey S et al. (2010) Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28:453-9
Connelly, Sarah F; Isley, Beth A; Baker, Cheryl H et al. (2010) Loss of tyrosine phosphatase-dependent inhibition promotes activation of tyrosine kinase c-Src in detached pancreatic cells. Mol Carcinog 49:1007-21
Kim, M P; Park, S I; Kopetz, S et al. (2009) Src family kinases as mediators of endothelial permeability: effects on inflammation and metastasis. Cell Tissue Res 335:249-59
Kopetz, Scott; Lesslie, Donald P; Dallas, Nikolas A et al. (2009) Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. Cancer Res 69:3842-9
Trepel, Martin; Stoneham, Charlotte A; Eleftherohorinou, Hariklia et al. (2009) A heterotypic bystander effect for tumor cell killing after adeno-associated virus/phage-mediated, vascular-targeted suicide gene transfer. Mol Cancer Ther 8:2383-91
Ng, Chaan S; Kodama, Yoshihisa; Mullani, Nizar A et al. (2009) Tumor blood flow measured by perfusion computed tomography and 15O-labeled water positron emission tomography: a comparison study. J Comput Assist Tomogr 33:460-5
Wang, Wei; Shao, Ruping; Wu, Qingping et al. (2009) Targeting gelatinases with a near-infrared fluorescent cyclic His-Try-Gly-Phe peptide. Mol Imaging Biol 11:424-33
Nie, Jing; Chang, Benny; Traktuev, Dmitry O et al. (2008) IFATS collection: Combinatorial peptides identify alpha5beta1 integrin as a receptor for the matricellular protein SPARC on adipose stromal cells. Stem Cells 26:2735-45
Urbanczyk-Pearson, Lauren M; Femia, Frank J; Smith, Jeffrey et al. (2008) Mechanistic investigation of beta-galactosidase-activated MR contrast agents. Inorg Chem 47:56-68

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