PDT and PIT with Chemotherapy for Treatment of 3D Ovarian Cancer Nodules Under Flow and Static Conditions
Mentor: Tayyaba Hasan, Ph.D. (MGH)
Metastases in ovarian cancer are associated with the poorest outcomes for patients. The cancer is able to spread to distant sites in the body by route of natural fluidic movement, resulting in aggressive disease that is hard to treat. A key biomarker in advanced ovarian cancer is the epidermal growth factor receptor (EGFR). Upregulation of EGFR has been shown in metastatic ovarian cancer with high proliferation and survival, and its effects on other factors enhance metastatic progression, resulting in poorer clinical outcome . A microfluidic platform was developed to culture cells in 3D under flow conditions. The flow model showed an increase in EGFR expression when compared to the static culture, indicating a more aggressive phenotype. Photodynamic therapy (PDT) is a photochemical approach that uses a light-activated photosensitizer (PS) and illumination by an appropriate wavelength of light to induce cytotoxicity of target cells by formation of a reactive oxygen species, or singlet oxygen . Combining a benzoporphyrin derivative (BPD) PS with an antibody creates a photo-immuno-conjugate (PIC) and thus initiates photo-immunotherapy (PIT). Specificity of killing is increased when PDT is performed with a PIC rather than a free photosensitizer. It is proven that the addition of chemotherapy drugs such as carboplatin to PIT greatly synergizes the anti-tumor and anti-metastatic effects of chemotherapeutics . OVCAR5 cells will be cultured in 3D nodules to investigate the effects of PDT, PIT, and PIT with chemotherapeutics on ovarian cancer cells under flow and non-flow conditions. The cells will be fluorescently labeled with mCherry, which will indicate presence of cells upon imaging. PDT will be performed with free photosensitizer (BPD), and PIT with the BPD photosensitizer coupled with an antibody. The PIC/PIT will include chemotherapeutic drugs as well. The overarching goal is to use 3D tumor models to show the effect of PDT/PIT + chemotherapy as effective in the treatment of metastatic ovarian cancer. References 1. Rizvi, I., et al., Flow induces epithelial-mesenchymal transition, cellular heterogeneity and biomarker modulation in 3D ovarian cancer nodules. Proceedings of the National Academy of Sciences, 2013. 110(22): p. E1974-E1983. 2. Celli, J.P., et al., Imaging and photodynamic therapy: mechanisms, monitoring, and optimization. Chemical reviews, 2010. 110(5): p. 2795-2838. 3. Rizvi, I., et al., Synergistic enhancement of carboplatin efficacy with photodynamic therapy in a three-dimensional model for micrometastatic ovarian cancer. Cancer research, 2010. 70(22): p. 9319-9328.
Figure: OVCAR-5 cells in 3D static culture (A). OVCAR-5 cells cultured under flow in microfluidic platform (B) . Expression of EGFR in flow and non-flow models. EGFR expression is greatly upregulated in the flow model. (C). Graph shows the percent of viable area of tumor nodule in cells treated with carboplatin only, PDT only, and PDT+ carboplatin. The data supports the synergistic effect of PDT+ carboplatin on tumor nodules (D) . Depiction of a PIC being irradiated with light (hv). (E). Combination of PDT/PIT+ chemotherapy has a promising outlook in treatment of ovarian cancer. Source: