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 anti-proliferation. 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-1) blockade therapy further implicate VEGF as an important regulator of this process. These studies indicate that therapies inhibiting EGF-R signaling have a significant anti-tumor 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, rate 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 angiogeneic factor production in tumor cells growing in vitro and in nude mice. Finally, we will validate and correlate the surrogate markers developed pre-clinically 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 assist 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.
|Effective start/end date||1/1/01 → 12/31/08|
- Cardiology and Cardiovascular Medicine
- Radiology Nuclear Medicine and imaging
- Cancer Research
- Statistics and Probability
- Pathology and Forensic Medicine