Abstract A23: Verteporfin as a new treatment paradigm for platinum-resistant ovarian cancer cells

Abstract

Abstract Ovarian cancer is the most lethal of the gynecologic malignancies and has poor survival rates due to a combination of diagnosis at advanced stages and disease recurrence due to platinum chemotherapy resistance. It is of utmost importance that novel chemotherapeutic agents are identified to increase or restore chemosensitization to platinum-based chemotherapy. Verteporfin (VP, VisudyneTM) is a benzoporphyrin derivative used for treating adult macular degeneration. Verteporfin has recently been identified as an inhibitor of YAP/TEAD interaction. Yes-associated protein (YAP), the main downstream target of the HIPPO pathway, plays an important role in cell proliferation and apoptosis. We investigated the efficacy of VP alone or in combination with cisplatin (CDDP) or carboplatin (CP) or paclitaxel (Taxol) on two serous ovarian cancer cell lines (OV90, COV504). The effect of VP, CDDP, CP or Taxol was studied either alone or in combination after 72 hours of treatment. Cell viability-based cytotoxicity measurements indicate dose-dependent increase in cytotoxicity for all the drugs. IC50 values of the drugs were calculated based on dose-effect curves using Compusyn software following the Chou-Talalay method. For OV90 cells, the calculated IC50 values were 29.33μM for VP, 2.17μM for cisplatin, 96.21μM for carboplatin, and 89.05μM for paclitaxel. For COV504 cells, the calculated IC50 values were 8.37μM for VP, 1.79μM for cisplatin, 117.23μM for carboplatin, and 7.16μM for paclitaxel. Based on the IC50 values of single agents, we performed cell proliferation assay using VP and CDDP/CP/Taxol in combination. We observed synergistic effects of VP with CDDP/CP/Taxol based on combination index plots. Based on the dose-reduction index (DRI) values of the drugs in combination treatments, we performed cytotoxicity and invasion assays. The combination treatments of these drugs at DRI values induced cytotoxicity and inhibited invasion of cancer cells. To check the chemosensitization of VP in cancer cells, we used cisplatin-resistant ovarian cancer cells, A2780Cis. Similar to ovarian cancer cells, VP effectively inhibited proliferation of A2780Cis cells. Based on these results, we hypothesize that VP is inducing chemosensitivity in platinum resistant ovarian cancer cells and increasing the efficacy of either platin drugs or Taxol. We suggest that our preclinical data in combination with previously available human safety data support the study of VP in combination with platinum in a clinical phase 2 trial of serous ovarian cancer patients. Note: This abstract was not presented at the conference. Citation Format: Radhika P. Gogoi, Venkata Ramesh Dasari. Verteporfin as a new treatment paradigm for platinum-resistant ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A23.