Abstract 1637: Depletion of tumor stroma with Smoothened inhibition leads to altered epithelial differentiation and paradoxical acceleration of pancreatic tumorigenesis.
Authors: Oberstein Paul E. , Thomas Dafydd H. , Palermo Carmine F. , Sastra Stephen A. , Olive Kenneth P. 
Published: August 2014

Pancreatic ductal adenocarcinoma (PDA) is highly resistant to conventional chemotherapy and is rapidly fatal. PDA is characterized by the presence of abundant stromal proliferation which can be replicated in mouse models. This stromal component is driven by paracrine signals from the neoplastic epithelium. These signals include Sonic Hedgehog (SHH), a secreted ligand of the hedgehog pathway which is overexpressed in PDA epithelium and signals through Smoothened to activate Gli family transcription factors and drive stromal proliferation. We have previously demonstrated that pharmacologic inhibition of Smoothened depletes tumor stroma and facilitates deliver of chemotherapy to the tumor epithelium. This approach led to prolonged survival in a genetically engineered mouse model of PDA (KPC mouse) and led to clinical trials utilizing this approach.

Unfortunately, combination therapy with Smoothened inhibition and chemotherapy did not improve survival in subsequent clinical trials. In an effort to explain this discrepancy we initiated therapy of KPC mice with a Smoothened inhibitor alone at 8 weeks of age. We hypothesized that unlike in previous studies that utilized advanced tumors and thus evaluated relatively short treatment effects, this design would allow us to investigate the long term effect of stromal depletion. Surprisingly, prolonged Smoothened inhibition led to an acceleration of pancreatic tumorigenesis and decreased survival to 122 days compared to 155 days in historic controls (p&lt;.001 by log-rank test.) The tumors observed in treated mice were notable for their lack of stroma and high vascularity. Additionally, a change in differentiation state was noted in these tumors with nearly all tumors demonstrating poor or undifferentiated morphology.

During pancreatic development, SHH and other signals from nearby stromal cells designate the exocrine fate of epithelial progenitor cells, and support exocrine growth. Tumor stromal cells may play a similar pro-differentiation role in pancreatic cancer, resulting in the well- to moderately-differentiated ductal morphology that is typically observed in human PDA. Previous studies have shown that tumors that are poorly differentiated by histologic exam or “quasi-mesenchymal” by gene expression pattern are associated with significantly shorter overall survival. Taken together, these data suggest that the loss of stromal signals following prolonged inhibition of Smoothened may result in de-differentiation of neoplastic epithelial cells and lead to more aggressive tumors. These findings may explain the clinical trial results and may inform future attempts to modulate stromal-epithelial interactions in PDA.

Citation Format: Paul E. Oberstein, Dafydd H. Thomas, Carmine F. Palermo, Stephen A. Sastra, Kenneth P. Olive. Depletion of tumor stroma with Smoothened inhibition leads to altered epithelial differentiation and paradoxical acceleration of pancreatic tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1637. doi:10.1158/1538-7445.AM2013-1637