Thesis (Ph. D.)--University of Wisconsin--Madison, 1975. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

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Met has been found to be over-expressed in human breast cancer, correlating with disease progression and poor prognosis. Src and Stat3 have also been found to be over-expressed in many human cancers, including breast. Met, Src and Stat3 have all been proposed as potential therapeutic targets for basal-like breast cancer (BLBC), an aggressive subtype of breast cancer defined by expression of Cytokeratin 5/6 and epidermal growth factor receptor (EGFR). In addition, Src and Stat3 have been shown to act co-operatively to promote the transcription of HGF, while Stat3 can also increase the expression of Met mRNA. The goal of this study was to determine if Src and Stat3 affect the activity and expression of Met in human breast cancer. The study has also assessed the functional effect of Src, Stat3 and Met blockade on cultured breast cancer cells and a breast tumour xenograft model. Finally, a preliminary assessment was performed of Src, Stat3 and Met as biomarkers for distinct clinico-pathological parameters in a breast cancer cohort, and of the prognostic value of these markers in an online, publically available, breast cancer database. The results demonstrate a density- and Src-dependent increase in Met protein levels in cultured cells, through Stat3 (Src/Stat3-Met). Furthermore Src, Stat3 or Met blockade in tumour xenograft models were found to inhibit primary tumour growth. However treatment with Dasatinib (Src inhibitor) or Met knockdown had no effect on pulmonary metastasis, while Stat3 inhibition (CPA7) increased metastasis, indicating that Stat3 may have a protective function in metastatic breast cancer. Finally Src and the Stat3 target gene, Cyclin D1, were found to correlate with distinct clinico-pathological parameters in a human breast cancer cohort. My study has identified a Src/Stat3-regulated Met pathway in human invasive breast cancer. These findings further provide insight into the minimal effectiveness of Src and Met inhibitors as single agent therapeutics in breast cancer treatment. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2014-01-23 23:36:06.52

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Ovarian high-grade serous cancer (HGSC) is the most lethal gynecologic malignancy and well-characterized models may improve patient outcomes. Patient-derived xenografts (PDXs) recapitulate disease heterogeneity; however, to be useful in predicting response to novel chemotherapeutics, they must reflect the response of the donor tissue to standard chemotherapy. The objectives of this study were: first, to evaluate the response of PDXs’ to platinum therapy and compare this response to that of the donor; and second, to determine whether treatment with chemotherapy enriches for tumourigenic cells. Eighteen samples formed tumours in the mammary fat pads of NOD-Scid-IL2Rγnull mice and were treated with Carboplatin. There was a 100% concordance between sample status and PDXs response to chemotherapy. HGS histology was confirmed for all cases. A conclusion regarding post-chemotherapy tumourigenicity could not be made due to inadequate statistical power. PDXs represent useful tools for evaluation of novel therapies and identification of patients who are platinum-resistant/sensitive.

Ovarian high-grade serous cancer (HGSC) is the most lethal gynecologic malignancy and well-characterized models may improve patient outcomes. Patient-derived xenografts (PDXs) recapitulate disease heterogeneity; however, to be useful in predicting response to novel chemotherapeutics, they must reflect the response of the donor tissue to standard chemotherapy. The objectives of this study were: first, to evaluate the response of PDXs’ to platinum therapy and compare this response to that of the donor; and second, to determine whether treatment with chemotherapy enriches for tumourigenic cells. Eighteen samples formed tumours in the mammary fat pads of NOD-Scid-IL2Rγnull mice and were treated with Carboplatin. There was a 100% concordance between sample status and PDXs response to chemotherapy. HGS histology was confirmed for all cases. A conclusion regarding post-chemotherapy tumourigenicity could not be made due to inadequate statistical power. PDXs represent useful tools for evaluation of novel therapies and identification of patients who are platinum-resistant/sensitive.

Die Behandlung von Krebserkrankungen wurde in den letzten Jahren von zwei großen Trends beeinflusst. Statt zytotoxischer Therapien, wurden zielgerichtete monoklonale Antikörper entwickelt. Zudem verstärkten sich die Bemühungen in der Entwicklung prädiktiver Biomarker, die die Stratifizierung von Patienten vor der Behandlung ermöglichen. Obwohl hunderte von zielgerichteten Krebsmedikamenten entwickelt wurden, erreichten nur wenige davon eine Zulassung. Grund hierfür ist die noch hohe Ausfallrate bei der „Übersetzung“ von vielversprechenden präklinischen Daten, die mit Krebs-Zelllinien und Xenograft-Modellen von Krebs-Zelllinien erlangt wurden, in positive klinische Phase II- und Phase III-Daten. Das Ziel der Forschung ist es, neue zielgerichtete Therapien und gleichzeitig prädiktive Marker, mit Hilfe von verbesserten präklinischen Tumormodellen zu entwickeln. Ein Panel von 133 Xenograftmodellen aller vier UICC-Stadien wurde etabliert. Zur Überprüfung dieses Modells wurde die Wirksamkeit von Cetuximab, Bevacizumab und Oxaliplatin getestet. Für dieses Experiment benutzten wir 67 Xenograft-Modelle, die aus chemonaiven CRC-Patienten entwickelt wurden. Die Behandlung mit einer Cetuximab-Monotherapie ergab eine objektive Ansprechrate von 27%. Dank dieser hohen Ansprechrate, konnten wir das verfügbare Tumorgewebe zur Vorhersage der Reaktion auf die Anti-EGFR-Antikörper in den Xenograft-Modellen verwenden. Wir untersuchten die Genauigkeit von Mutations-Markern (KRAS, BRAF und PIK3CA) kombiniert mit RNA-Expressionsdaten von Amphiregulin und Epiregulin. Weiterhin wurden neue prädiktive Marker-Kombinationen, basierend auf einer mRNA- und microRNA- Expressionsanalyse, ermittelt. Aufgrund der erfolgreichen Nachbildung der klinischen Situation in unserem Panel von Xenograft-Modellen, zeigt dieser Modellansatz vielversprechendes Potenzial für eine zukünftige Anwendung in der Erprobung neuartiger Krebsmedikamente und der Entwicklung von prädiktiven Biomarkern. / Over the last ten years two major trends have influenced drug development. Instead of cytotoxic therapies a variety of targeted monoclonal antibodies have been developed. In parallel, higher attention has been paid to the identification and validation of predictive markers, which allow the stratification of patients prior to the treatment. Hundreds of targeted cancer drugs have been developed, but only a few have been approved. Despite these two trends, there is still a high rate of failure in translating promising preclinical data obtained with cancer cell lines and xenograft models derived from cancer cell lines into positive clinical phase II and phase III data. The goal of the scientific community is to develop novel targeted therapies and predictive biomarkers using better preclinical tumour models. To bridge the gap between preclinical and clinical development a panel of 133 patients-derived CRC xenografts of all four UICC stages was established. An efficacy of cetuximab, bevacizumab and oxaliplatin was tested in the subset of 67 models. In the treatment experiment with cetuximab monotherapy an objective response rate of 27% was obtained. This high response rate allowed the use of the tumour tissues for evaluating molecular markers for predicting response to the anti-EGFR antibody in the xenograft models. The accuracy of three mutation markers including KRAS, BRAF and PIK3CA was investigated in combination with RNA expression levels of two EGFR ligands – amphiregulin and epiregulin. Novel predictive markers panels based on gene expression profiling of mRNA and microRNA were also tested and compared with the established biomarkers. Successful reconstruction of the clinical situation in the panel of xenograft models proves their potential for future use in testing of novel anti-cancer drugs. Moreover, their broad molecular characterization allows the simultaneous development of predictive biomarkers along with the testing of novel cancer drugs.