(G-279) Evaluation of Repurposing Anti-Parasite Drugs for Ovarian Cancer from Cell to Animal Level Using Optical Coherence Tomography

Introduction:: Effective treatment for recurrent epithelial ovarian cancer is a major, unmet public health need as the response rates of the patients are often low with the traditional chemotherapy. Repurposing drugs is an increasingly popular strategy in oncology due to the financial and logistical constraints of new drug development. Recently, anti-parasitic drugs such as mebendazole have surfaced as repurposed oncology drugs and showed promise in treating multiple types of tumors. The anti-parasitic drugs, fenbendazole and mebendazole, are in the benzimidazole class and have been FDA-approved to treat pinworm and other helminthic. Although these seem to be the mechanisms of action in parasites, the exact mechanism of their anti-cancer effect in human cells is unknown.

Materials and Methods:: In multicellular tumor spheroids (MCTs) model, parent OVCAR8 (wild type, WT) and CPR OVCAR8 (cisplatin-resistant cells) MCTs were treated by saline (control group), fenbendazole, mebendazole, and the corresponding combination. 80 MCTs in total were imaged by a polarization-sensitive optical coherence tomography (PS-OCT) system every two days within 10 days. In the animal model, the mice implanting OVCAR8 tumors were scanned by PS-OCT before, one week after, and three weeks after treatments of saline (control group), fenbendazole, mebendazole, and the corresponding combination. Two-dimensional (2D) and three-dimensional (3D) imaging modes were used to provide cross-sectional, enface, and spatial information of MCTs and tumors within mice in vivo for monitoring the change of morphology and tissues distribution at different time points of treatment. Three polarization parameters (phase retardation, optic axis direction, and degree of polarization uniformity-DOPU) and three Stokes parameters (Q, U, and V) were utilized for multi-parameter image analyses and quantification. After OCT imaging, the corresponding tissues were processed by standard histological staining.

Results, Conclusions, and Discussions:: In this study, we observed that the combination of fenbendazole and mebendazole showed a significant inhabitation to MCTs growth in volume and a significant increase in necrosis compared to the single use of either fenbendazole or mebendazole despite each of them had an inhabitation of the morphology of MCTs. These treatments caused a significant increasing in the uniformity degree within MCTs compared WT and CPR MCTs. Moreover, PS-OCT found that some collagens existed within the MCTs treated by fenbendazole, mebendazole, and the combination, which demonstrated that these treatments caused the change of internal tissues within MCTs. We found that the volume size and weight of ovarian tumors within mice body were significantly smaller than the control group. Fenbendazole and mebendazole also singly inhibited the volume size of tumors compared to the control mice. Besides, the necrotic tissues and high uniformity tissues within MCTs which were treated by the combination of fenbendazole and mebendazole were significantly more than control mice tumors despite fenbendazole and mebendazole singly caused more necrosis and higher uniformity tissues. Our results confirmed that FDA-approved anti-parasite drugs fenbendazole, mebendazole, and the combination significantly inhibited the volume and tissue growth from PS-OCT images in cell and animal levels.

Acknowledgements (Optional): : This work was supported by grants from the University of Oklahoma Health Sciences Center (3P30CA225520), Faculty Investment Program from University of Oklahoma, Institutional Research Grant number IRG-19-142-01 from the American Cancer Society, National Science Foundation (OIA-2132161, 2238648), National Institute of Health (R01DK133717), Oklahoma Shared Clinical and Translational Resources (NIGMS U54GM104938), Oklahoma Center for the Advancement of Science and Technology (HR23-071), and the medical imaging COBRE (P20 GM135009). Histology service provided by the Tissue Pathology Shared Resource was supported in part by the National Institute of General Medical Sciences COBRE Grant P20GM103639 and National Cancer Institute Grant P30CA225520 of the National Institutes of Health.

References (Optional): :