Thesis (Ph. D.)--University of Virginia, 1999. / Includes bibliographical references (p. 171-256). Also available online through Digital Dissertations.

Thesis (Ph. D.)--University of Missouri-Columbia, 1999. / Typescript. Vita. Includes bibliographical references (leaves 71-83). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 1999. / Typescript. Vita. Includes bibliographical references (leaves 71-83). Also available on the Internet.

Thesis (Ph. D.)--Case Western Reserve University, 2006. / [School of Medicine] Department of Pathology. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Thesis (Ph. D.)--Ohio State University, 2005. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2006 September 20

Thesis (Ph.D.)--McMaster University, 2004. / Advisor: William J. Muler. Includes bibliographical references (leaves 171-199). Also available online.

Introduction: The incidence of oesophageal cancer (OC) is increasing. Targeted therapies are being investigated, as chemotherapy in advanced OC achieves only 50% response rates and confers significant toxicity. TRANS-COG is a sub-study of COG, the only randomised trial of the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib versus placebo in patients with advanced OC. Aim and Methods: The aim of TRANS-COG is to identify biomarkers for predicting response to gefitinib by investigating the frequency of mutations of EGFR pathway members and EGFR gene copy number gain (CNG) by Fluorescence In Situ Hybridisation (FISH). Results: No EGFR mutations were identified, frequency of other pathway member mutations are as follows: KRAS 3.6%, PI3KCA 3.2%, BRAF 0.6%. The frequency of EGFR CNG was 13.5%. There were two cases of combined EGFR CNG and KRAS mutation 0.3%.Patients with EGFR CNG tumours had improved OS with gefitinib compared to placebo, log rank p=0.033, HR 0.523 (95%CI 0.285-0.962). Those with EGFR high CNG (amplification) also had improved OS with gefitinib, median OS 4.40 months vs median OS 1.71 months for placebo log rank p=0.004, HR 0.184 (95% CI 0.052-0.653). Mutation of KRAS conferred poor prognosis, independent of treatment received; median OS 3.614 months in KRAS wild type vs 1.741 months in KRAS mutated tumours, log rank p=0.023, HR 1.8153 (95% CI 1.078 3.187). A novel KRAS codon 61 mutation, Q61L, was also identified. Conclusion: 21.18% of patients have dysregulation of the EGFR pathway, these abnormalities represent realistic therapeutic targets. This analysis demonstrates clinical utility of EGFR CNG as a predictive biomarker of gefitinib response.

The Tec family tyrosine kinases Itk, Tec and Rlk are expressed in T cells. Previous studies have established that these kinases are critical for TCR signaling, leading to the activation of PLCγ1. To further understand the functions of Tec kinases in T cell activation, we took three different approaches. First, we performed a thorough analysis of CD28-mediated signaling events and functional responses with purified naïve T cells from Itk-/- mice and a highly controlled stimulation system. Data from this set of studies definitively demonstrate that CD28 costimulation functions efficiently in naïve CD4+ T cells in the absence of Itk. Second, in order to further study the functions of Tec kinases in vivo, we generated transgenic mouse lines expressing a kinase-dead (KD) mutant of Tec on the Itk-/-Rlk-/- background, hoping to study mice that are functionally deficient for all three Tec kinases. The results hint the importance of the Tec kinases in T cell development and/or survival. Finally, in order to identify potential transcriptional targets of Itk, we used microarray technology to compare global gene expression profiles of naïve and stimulated Itk-/- versus Itk+/- CD4+ T cells. This analysis provided a short list of differentially expressed genes in Itk-/- versus Itk+/- CD4 T cells, providing a starting point for further studies of Itk in T cell activation. Collectively, these studies clarified the role of Itk in CD28 signaling, revealed some unexpected aspects of Tec family kinases in T cells, and indicated potential targets of Itk-dependent signaling pathways in T cells.

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