Pancreatic cancer is one of the most aggressive and deadliest cancers, with only about 5% of patients surviving 5 years past the initial diagnosis. In over 80% of patients the cancer has already spread to distant organs at the time of diagnosis, making it difficult to treat. Most alarmingly, pancreatic cancer is the only cancer for which deaths are predicted to increase over the next few years. Despite advances with new chemotherapy combinations, overall survival outcomes are still dismal and require novel therapeutic approaches. Necuparanib (formerly M402) is a heparan sulfate-like molecule that binds and inhibits multiple heparin-binding growth factors, chemokines, adhesion molecules and enzymes involved in cancer progression and metastasis and as such modulates multiple elements of the tumor microenvironment. In order to further explore the mechanism of action for epithelial-stromal interactions affected by necuparanib, a 3-dimensional culture system mimicking pancreatic cancer was developed containing a co-culture of pancreatic tumor cells and pancreatic stellate cells, the most abundant stromal cell in the pancreas. In this culture system, pancreatic cancer cells form a tumor spheroid embedded in a matrix that is a mixture of type I collagen and basement membrane extract and contains pancreatic stellate cells. Notably, pancreatic cancer cells required the co-culture with pancreatic stellate cells to become invasive in vitro. Conditioned medium derived from pancreatic stellate cells could not mimic this effect indicating that soluble factors are not sufficient to cause invasion into surrounding matrix. Necuparanib inhibited the invasive behavior in a dose-dependent manner. The effect of pancreatic stellate cells on tumor cell invasion and the effect of necuparanib on stromal cells were further explored in this culture system. We showed an effect of necuparanib on proliferation, migration and invasion of pancreatic tumor cells. These studies aid in our understanding of the key biological targets and pathways responsible for necuparanib's anti-tumor effects and support biomarker discovery in the ongoing Phase 2 efficacy study in metastatic pancreatic cancer.

Citation Format: Silva Krause, Amanda Weyers, Katie Loveluck, Birgit Schultes. Necuparanib affects tumor progression and invasion in a 3D co-culture system of pancreatic cancer cells and stellate cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5499. doi:10.1158/1538-7445.AM2015-5499