A Primary 3D Culture Model for the High Throughput Ex-vivo Modeling of Ovarian Cancer Metastasis

SUMMARY

• Current high throughput screens for ovarian cancer drug discovery use monolayer cell culture on plastic, and problematically cannot accurately model the cross communication between the cancer cells and the tumor microenvironment that occur in vivo. The lack of effective models for ovarian cancer drug screening is responsible for the high attrition rate from screen hits to potent in vivo drug leads.
• The inventors developed a heterotypic, 3D organotypic culture system that enables evaluation of adhesion, migration, invasion, and proliferation of ovarian cancer cells in the context of in in vivo-like tumor microenvironment. The model is assembled using primary human omental fibroblasts, mesothelial cells, and extracellular matrices, on top of which cancer cell lines are cultured. 
• The invention is a 3D organotypic culture system that recapitulates the surface histology of the abdominal peritoneum, the primary site of ovarian cancer metastasis. The model is compatible with high throughput screening in both a 384 and 1536 well format for drug discovery campaigns.
• The inventors optimized and validated the culture system with multiple ovarian cancer cell lines (HeyA8, SKOV3ip1, Tyk-nu) by using the model to screen a 44,000-compound library for inhibitors of ovarian cancer metastasis, adhesion and migration. The lead compounds were validated in vivo with mouse models of ovarian cancer (see 19-T-011 for compounds).

FIGURE

(A) Overview of the 3D ovarian cancer culture model showing positioning of all cell types in the model and the ability to use the model to evaluate the efficacy of drug compounds. (B) Fluorescent images of the 3D HITS assay with fluorescent labeled mesothelial cells (blue) and fibroblasts (red) with SKOV3ip1 ovarian cancer cells (green). Scale bar represents 100um. Z-axis reconstruction of optical sections with orthogonal view of maximum intensity shown (45um scale).

ADVANTAGES

ADVANTAGES

• Models peritoneal metastasis (main site of ovarian cancer metastasis)
• Models in vivo activity in library screens
• Model accounts for fibroblast contribution to metastasis
• Compatible with high throughput screening
• Applicable to other cancers that metastasize to the peritoneal cavity (gastric, pancreatic, endometrial)

APPLICATIONS

• High throughput drug discovery (metastatic ovarian cancer)
• Research tool
• Personalized medicine

PUBLICATIONS

• Kenny, HA; et al. Use of a novel 3D culture model to elucidate the role of mesothelial cells, fibroblasts, and extra-cellular matrices on adhesion and invasion of ovarian cancer cells to the omentum. Int J Cancer. 2007 Oct 1; 121(7): 1463-72.
• Kenny, HA; et al. Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy. Nat Commun. 2015 Feb 5; 6:6220

September 15, 2019

Ready for use for research and drug discovery

Tangible property

Licensing

Ernst Lengyel