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Inhibition of Pancreatic Cancer Cell and Stroma Growth With a Downstream Hedgehog Antagonist
Kim C. Honselmann*, Moritz F. Pross, Ulrich F. Wellner, Hryhoriy Lapshyn, Ekaterina Petrova, Tobias Keck, Dirk Bausch
General Surgery, University of Luebeck, Luebeck, Germany

Pancreatic cancer is still a dismal disease today. Advances on effective chemotherapeutic agents have not led to significant clinical changes in survival yet. This is mostly due to a highly desmoplastic stroma, which seems to have different functions for the tumor, one being to promote tumor growth and chemo resistance. Paracrine Hedgehog (Hh) signaling is one key regulator of the tumor stroma, but not the cancer cells. This is why upstream Hh inhibition has not proven to be an effective chemotherapeutic agent against pancreatic cancer. But there is growing evidence for a non-canonical Hh-pathway in the tumor cells themselves. Therefore the aim of this study was to find out, if direct inhibition of the transcriptional factor GLI, a downstream Hh effector, harms pancreatic tumor cells and the tumor stroma, especially in comparison to inhibition of the upstream factor SHH.
Five pancreatic cancer cell lines were treated with the synthetic GLI inhibitor GANT-61 and assessed for viability in vitro. In the following in vivo experiments, we employed Panc1 or HPAF2 cells into a subcutaneous mouse model with athymic female nu/nu mice and treated them either with PBS, GANT-61 (40 mg/kg body weight) or 5E1 Antibody (300ug per mouse/per day) three times a week for 21 days. Tumor size was measured twice a week and tumors were harvested on day 21 for Immunohistochemistry and RNA-isolation. RT-PCR was done to evaluate the effect of GANT-61 and a hedgehog antibody 5E1 on the Hedgehog pathway genes in the stroma (mouse) and the tumor cells (human).
Tumor cell viability in all cell lines was reduced by up to 94.1% under treatment with GANT-61 in a concentration dependent manner. Tumor size was reduced in mice with Panc1 tumors treated with Gant 61 (69%) and 5E1 (48%) for 21 days (Fig 1). Tumors in mice with HPAF2 tumors were reduced by 64% (GANT-61) and by 85% (5E1) (Fig 1). Growth inhibition was most likely due to Hh pathway gene expression seen in both the tumor and stroma cells in GANT-61 treated mice. 5E1 demonstrated complete inhibition of the Hh pathway in the stroma but not in the tumor cells (Fig.2)
The Gli-antagonist GANT-61 was able to inhibit tumor growth by up to 69% in vivo. This effect was due to tumor cell and stroma Gli inhibition. Gant 61 could possibly be a new effective therapeutic agent in the fight against pancreatic cancer as it targets both the tumor stroma and the cancer cells. Proteomic analyses in order to find out the Gli effectors are underway.

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