Abstract NT-097: QUANTITATIVE HIGH-THROUGHPUT SCREENING USING AN ORGANOTYPIC MODEL IDENTIFIES TWO KINASE INHIBITORS THAT INHIBIT OVARIAN CANCER METASTASIS

Abstract

The cancer cells, stromal cells and stroma in the tumor microenvironment contribute to cancer metastasis and drug resistance. Therefore we applied an organotypic, robust and reliable assay for quantitative high throughput screening (qHTS) in drug discovery. This 1536-well HTS culture contains primary human mesothelial cells, fibroblasts, fibronectin and collagen type I and reproduces the human ovarian cancer (OvCa) metastatic microenvironment. The qHTS assay identifies small molecule compounds that inhibit OvCa adhesion/migration/invasion to the organotypic metastatic microenvironment. Over 44,000 small molecules were screened in the primary qHTS assay. A counter screen was performed to eliminate any compounds toxic to the mesothelial cells or fibroblasts within the metastatic microenvironment. The activity of hit compounds was confirmed using five OvCa cell lines, and validated in secondary in vitro and in vivo biological assays. The active compounds directly inhibit at least two of three OvCa functions: adhesion, invasion and growth. In vivo, these compounds prevent OvCa adhesion/invasion and metastasis, and improve survival in mouse models. Collectively, these data indicate that the three compounds, two tyrosine kinase inhibitors and one novel compound, identified using an complex organtoypic culture of the tumor microenvironment for qHTS are potential therapeutics for OvCa metastasis. Citation Format: Hilary A. Kenny, Madhu Lal, Min Shen, Dominik Nahotko, Sarah Fazal, Siquan Chen, Chun-Yi Chiang, Betul Kara, S. Diane Yamada, Kyle Brimacombe, Juan Marugan, Marc Ferrer and Ernst Lengyel. QUANTITATIVE HIGH-THROUGHPUT SCREENING USING AN ORGANOTYPIC MODEL IDENTIFIES TWO KINASE INHIBITORS THAT INHIBIT OVARIAN CANCER METASTASIS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-097.