October 7, 2019 | Jola Glotzer
Fighting metastatic ovarian cancer
CBC High-Throughput Screening (HTS) Award helps Hilary Kenny and Ernst Lengyel, UChicago, identify three promising ovarian cancer metastasis inhibitors
Until sensitive and reliable methods that allow early detection of the ovarian cancer in its still treatable stages become available, research efforts which focus on identifying new compounds with cancer anti-metastatic properties are of equal or potentially even greater importance as about 70% of women who are first diagnosed with this type of cancer present in already metastatic and hence almost always fatal stage.
In 2013, Hilary Kenny and Ernst Lengyel, UChicago, won a CBC HTS Award for the project “HTS Using an Organotypic Culture of Ovarian Cancer Metastasis.” The goal was to test whether a 3D culture system developed in Lengyel’s lab to mimic the in vivo tumor microenvironment could be utilized to screen for compounds inhibiting ovarian cancer cells metastatic properties such as adhesion, invasion and proliferation/growth.
In the current study recently published in Molecular Cancer Therapeutics, Kenny and Lengyel report identification of three compounds with anti-metastatic properties by using the HTS and the 3D organotypic culture system, followed by validation of the compounds in several other biological assays. These promising anti-metastatic compounds are two tyrosine kinase inhibitors, PP-121 and Milciclib, and a previously unreported compound, NCGC00117362. Kenny and Lengyel acknowledge the CBC HTS Award as having partially supported the published research.
The CBC congratulates all of the authors involved in this important work and wishes them further successes in moving the project forward!
Ernst Lengyel, MD, PhD, is Professor and Chairman of the Department of Obstetrics and Gynecology, section Gynecologic Oncology, at UChicago. Hilary Kenny, PhD, is a Research Assistant Professor in the same Department of Obstetrics and Gynecology at UChicago. In addition, Lengyel and Kenny are co-directors of the Ovarian Cancer Research Laboratory established at UChicago in 2004.
Publication attributed to the *CBC funding:
Kenny HA, Lal-Nag M, Shen M, Kara B, Nahotko DA, Wroblewski K, Fazal S, Chen S, Chiang CY, Chen YJ, Brimacombe KR, Marugan J, Ferrer M, Lengyel E. Quantitative high-throughput screening using an organotypic model identifies compounds that inhibit ovarian cancer metastasis. Mol Cancer Ther. 2019 Sep 27. [Epub ahead of print] (PubMed)
The tumor microenvironment (TME) is a key determinant of metastatic efficiency. We performed a quantitative high throughput screen (qHTS) of diverse medicinal-chemistry tractable scaffolds (44,420 compounds) and pharmacologically active small molecules (386 compounds) using a layered organotypic, robust assay representing the ovarian cancer (OvCa) metastatic TME. This 3D model contains primary human mesothelial cells, fibroblasts and extracellular matrix, to which fluorescently-labeled OvCa cells are added. Initially, 100 compounds inhibiting OvCa adhesion/invasion to the 3D model in a dose-dependent manner were identified. Of those, eight compounds were confirmed active in five high-grade serous OvCa cell lines, and were further validated in secondary in vitro and in vivo biological assays. Two tyrosine kinase inhibitors, PP-121 and Milciclib, and a previously unreported compound, NCGC00117362, were selected because they had potency at 1μΜ in vitro. Specifically, Milciclib and NCGC00117362 inhibited OvCa adhesion, invasion and proliferation, while PP-121 inhibited OvCa invasion and proliferation. Using in situ kinase profiling and cellular thermal shift assays, we found that Milciclib targeted Cdk2 and Cdk6, and PP-121 targeted mTOR. In vivo, all three compounds prevented OvCa adhesion/invasion and metastasis, prolonged survival and reduced omental tumor growth in an intervention study. To evaluate the clinical potential of NCGC00117362, structure-activity-relationship studies were performed. Four close analogs of NCGC00117362 efficiently inhibited cancer aggressiveness in vitro and metastasis in vivo. Collectively, these data show that a complex 3D culture of the TME is effective in qHTS. The three compounds identified have promise as therapeutics for prevention and treatment of OvCa metastasis.
We thank Gail Isenberg for editing the manuscript. This work was supported by the Ovarian Cancer Research Fund Alliance (OCRFA)- Liz Tilberis Early Career Award 545674 (H Kenny), an HTS award from the Chicago Biomedical Consortium with funding from the Searle Funds at The Chicago Community Trust (E Lengyel and H Kenny), Bears Care – the charitable beneficiary of the Chicago Bears Football Club (EL and HAK), R01CA111882 (E Lengyel), and by the Intramural Research Program (Division of Preclinical Innovation, National Center for Advancing Translational Sciences). The Cellular Screening Center and Human Tissue Resource Center Cores at the University of Chicago are funded by the Cancer Center Support Grant (P30CA014599).
Featured CBC Community member(s):
ARTICLES PUBLISHED IN THE PAST ABOUT THE FEATURED CBC COMMUNITY MEMBER(S):
May 21, 2019
▸ Cells surrounding the cancer promote its spread
Two CBC Awardees, Ernst Lengyel and Raymond Moellering, UChicago, contribute to recent research published in Nature about the role of stroma in facilitating metastasis of ovarian cancer cells
May 4, 2019
▸ Consider slimming down!
CBC affiliate Ernst Lengyel, UChicago, comments in U.S.News on the rise of obesity-related cancer
February 19, 2019
▸ CT45, or cancer/testis antigen 45
Past CBC Awardee, Ernst Lengyel, UChicago, contributes to the discovery of a biomarker that can help predict response to therapy in patient suffering from ovarian cancer
September 28, 2018
▸ Glycogen fuels ovarian cancer spread
Three CBC awardees, Ernst Lengyel, Hilary Kenny and Yilin Zhang, UChicago, co-author new publication in Cell Metabolism