Date of Award
Master of Science
Molecular Biology Microbiology and Biochemistry
AN ABSTRACT OF THE THESIS OF LISA DANIELLE VOLK, for the Master of Science degree in Molecular Biology, Microbiology, and Biochemistry presented on October 30, 2008, at Southern Illinois University Carbondale, School of Medicine, Springfield. TITLE: THE COMBINATION OF NAB-PACLITAXEL AND BEVACIZUMAB THERAPY SYNERGISTICALLY IMPROVES TUMOR RESPONSE IN XENOGRAFT BREAST CANCER MODELS MAJOR PROFESSOR: Dr. Sophia Ran Breast cancer is the second leading cause of death for women in the United States. Current breast cancer therapies frequently achieve only partial tumor response, resulting in tumor recurrence, metastasis, and mortality. Tumor recurrence and progression in spite of chemotherapy can enhance angiogenesis and activation of pro-survival mechanisms, thus counteracting death of tumor cells. We reasoned that vascular endothelial growth factor A (VEGF-A), the potent pro-angiogenic factor, could be induced in tumors to counteract therapy-induced cytotoxicity. We hypothesized that combining a potent chemotherapeutic drug such as nab-paclitaxel with anti-VEGF-A antibody, bevacizumab, would significantly improve treatment outcome of advanced metastatic breast tumors. The first goal of this study was to test this hypothesis in orthotopic mouse models. The second goal of this study was to delineate the underlying mechanisms that promote tumor recurrence and metastasis. To achieve these goals, metastatic human breast carcinoma lines tagged with firefly luciferase, MDA-MB-231 Luc+ (231-Luc+) and the MDA-MB-435 Luc+(435-Luc+), were orthotopically implanted, grown to advanced (450 mm3) tumor sizes, and then treated with single or combined nab-paclitaxel (30 mg/kg) and bevacizumab (4 mg/kg). The endpoints of the study were the rate of tumor growth, incidence and burden of metastases, tumor blood vessel density (BVD) and activation status of angiogenic, inflammatory, and survival pathways. Eradication of advanced 231-Luc+ tumors and both lymphatic and pulmonary metastasis were observed after two cycles of combination therapy. Time course analysis of 231-Luc+ metastatic dissemination revealed early metastases to the ipsilateral lymph nodes from primary tumors occurred in 100% of the mice once tumors reached 250 mm3. Because the therapy was applied to mice with tumors equal or larger than 450mm3, this finding indicates that combined therapy eradicated pre-existing metastatic lesions rather than prevented their spread from the primary site. Similar regimen in the model of advanced 435-Luc+ tumors demonstrated clear benefits for the combined therapy over monotherapies, but did not eradicate tumors or metastases. On the molecular level, we found that nab-paclitaxel therapy increases expression of VEGF-A, phosphorylated-NF-B (p50), p-AKT, and bcl-2 proteins in cultured cells as wells as in the 231-Luc+ tumor model in vivo. Consistent with¬¬¬ elevated VEGF-A, nab-paclitaxel also induced a dose-dependent increase in blood vascular density. Activation of angiogenic, inflammatory (p-NF-B) and survival pathways by nab-paclitaxel might account for resistance to cytotoxic effect of paclitaxel therapy. This study results strongly support combining nab-paclitaxel and bevacizumab and suggest that this strategy applied to human subjects can eradicate advanced primary tumors and pre-existing metastases.
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