A multi-faceted approach to the detection and treatment of pancreatic cancer
LaConti, Joseph James.
Thesis (Ph.D.)--Georgetown University, 2010.; Includes bibliographical references.; Text (Electronic thesis) in PDF format. Pancreatic cancer is a devastating disease that lacks suitable early detection or treatment stategies to improve patient outcomes. The stages of progression towards human pancreatic cancer are recapitulated faithfully by directing the expression of oncogenic Kras to progenitor cells in the mouse pancreas. We utilized this model to investigate 1) the use of microRNA as a circulating biomarker of disease, 2) the inhibition of a tyrosine kinase to prevent cancer progression, and 3) that pancreatic cancer produces a metabolite profile in the circulation that can identify individuals with the disease.; Changes in miR expression patterns during progression of normal tissues to premalignancy (PanIN) and pancreatic adenocarcinoma (PDAC) in the p48-Cre/LSL-KrasG12D mouse model mirrors the miR changes observed in human pancreatic cancer tissues. miR-148a and miR-375 expression were found decreased whereas miR-10, miR-21, miR-100 and miR-155 were increased when comparing normal tissues, premalignant lesions and invasive carcinoma in the mouse model. miR-10, miR-21 and miR-155 were also found elevated in the serum of mice with pancreatic cancer relative to controls. Quantitation of microRNAs in plasma samples from patients with pancreatic cancer showed increased concentrations of miR-10, miR-21, miR-155 and miR-223 in contrast to patients with colon or liver cancers.; Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor expressed in PanIN as well as PDAC. We have developed an antagonistic mouse monoclonal IgG antibody to the ALK receptor (anti-ALK IgG). We used a quantum dot labeled anti-ALK IgG for the fluorescent visualization of pancreatic cancer cell allografts in nude mice. Anti-ALK IgG treatment was most effective at preventing the progression of late PanIN to PDAC, with 8.3% of antibody treated mice harboring PDAC compared to 33.3% of saline treated control mice. Metastasis was also prevented in mice treated with antibody. Anti-ALK IgG treatment increased apoptosis through inhibition of Stat3 activation.; We performed a global survey of metabolites detectable in the circulation of KrasG12D transgenic mice and humans with pancreatic cancer. Ultra Performance Liquid Chromatography (UPLC) coupled to time-of-flight mass spectrometry (TOFMS) detected metabolites in serum that with multivariate data analysis could separate individual mice and humans with and without pancreatic cancer.
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