(82d) A 3D Biomaterial Model for Patient-Derived Ovarian Cancer Drug Screening

Ovarian Cancer (OvCa) is poorly understood and has many challenges, including poor screening techniques, late diagnosis and lack of effective second line therapy. Recurrence rate after first line therapy (surgery + platinum-based chemotherapy) is more than 70%. There is a need for a second line therapy, but there have only been two drug approvals by the FDA since 2006 (Olaparib & Bevacizumab). 3D culture systems that mimic the peritoneal microenvironment of progressed OvCa could provide important insights into OvCa drug response, and potentially help the field find new, more efficacious treatments; however, there are very few studies describing 3D models for OvCa.

A significant number of drugs work well during in vitro preclinical trials, but fail in later stages (animal models or Phase I-II clinical trials). We hypothesize this is because 2D models used in most preclinical studies are inaccurate representations of OvCa. We hypothesize that 3D models can more accurately predict the usefulness of a drug, leading to fewer false leads, and fewer animal models or clinical studies which test drug candidates that will ultimately fail. Thus, 3D models of OvCa for drug screening can provide significant savings in time and resources to researchers in the industry and academia. In this study, we evaluate response to three chemotherapeutic drugs (cisplatin, carboplatin, and paclitaxel) and one targeted drug (sorafenib) of two OvCa cells lines (SKOV-3 and OVCAR-3), both on plastic surfaces and 2D gel surfaces coated with collagen. 2D gels were made by co-polymerization of poly(ethylene glycol) dimethacrylate (PEG) and the zwitterion 2-Methacryloyloxyethyl phosphorylcholine (PC) [1, 2] . We also evaluate the response to the chemotherapeutic drugs of patient ascites-derived cells on plastic, and patient ascites- derived spheroids on 3D gels obtained from UMass Medical School. For the 3D gels, spheroids were encapsulated in poly(ethylene glycol)-Maleimide (PEG-Mal) gels. PEG-Mal prepolymer solution, which contains spheroids, was crosslinked by PEG-dithiol. We measured drug response by using the CellTiter-Glo ATP assay and the required concentration of drug to kill 50% of the cells (IC₅₀) was calculated.

Thus far, our results show that SKOV-3 and OVCAR-3 are more resistant in 2D gels than plastic for all the drugs and combination of cisplatin+paclitaxel, and carboplatin+sorafenib. We also showed that patient ascites are more resistant than SKOV-3 and OVCAR-3 to cisplatin, paclitaxel, cisplatin+paclitaxel on plastic. Most importantly, spheroids encapsulated in 3D gels are more resistant than patient ascites-derived cells on plastic (where cells cannot be seeded as spheroids). This is a possible confirmation that 2D in vitro models show inaccurately high efficacies of cancer drugs, while more realistic 3D in vitro models are able to better represent drug resistance mechanisms found in vivo. The 3D culture system will be used to test drug resistance of multiple patient samples and we will validate our results with an in vivo model.

References

1. Herrick, W.G., et al., PEG-phosphorylcholine hydrogels as tunable and versatile platforms for mechanobiology. Biomacromolecules, 2013. 14(7): p. 2294-2304.

2. Nguyen, T.V., et al., Sorafenib resistance and JNK signaling in carcinoma during extracellular matrix stiffening. Biomaterials, 2014. 35(22): p. 5749-5759.