| The translational potential of new therapeutic strategies for cancer is limited, in part, by a lack of biological models that capture important aspects of tumor growth and treatment response. It is also becoming increasingly evident that no single treatment will be curative for this complex disease. Rationally-designed combination regimens that impact multiple targets provide the best hope of improving clinical outcomes. Rapidly identifying treatments that cooperatively enhance efficacy from the vast library of candidate interventions is not feasible with current systems. There is a vital, unmet need to create cell-based research platforms that more accurately mimic the complex biology of human tumors than monolayer cultures, while providing the ability to screen therapeutic combinations more rapidly than animal models.;This thesis introduces an in vitro 3D tumor model for metastatic ovarian cancer, which is the fifth leading cause of cancer-related deaths among women in the United States and is the most lethal gynecologic malignancy. OVCAR5 cells were overlaid on Growth Factor Reduced-Matrigel(TM) to represent unresectable ovarian micronodules that are typically managed with chemotherapy and often develop into lethal recurrent disease. In conjunction with quantitative image analysis routines developed to batch-process large datasets, this platform serves as a high-throughput reporter for treatment response. This system is used to assess mechanism-based combination regimens with photodynamic therapy (PDT), a photophysical cytotoxic modality that sensitizes ovarian cancer cells to chemo and biologic agents, and has shown clinical promise for treating advanced-stage ovarian cancer. Our data reveal heterogeneous tumor growth driven by proliferation, migration, and assembly. PDT disrupts micronodular architecture and synergistically enhances the efficacy of low-dose carboplatin in a sequence-dependent manner. A passage-dependent synergistic response with PDT and Erbitux (C225) was also demonstrated for the first time in an in vitro system. Sophisticated platforms, such as the one described here, could focus valuable resources for animal and patient tissue studies on the most effective regimens, potentially improving translational efficiency. Future multicellular 3D models will be developed with customizable synthetic matrices and will incorporate stromal signaling partners using novel cell ejection technologies. The principles described here could be used to design and evaluate mechanism-based therapeutic options for a broad spectrum of solid tumors. |
