Abstract PR01: Paradoxical acceleration of pancreatic tumorigenesis through Smoothened inhibition: A post-clinical trial in genetically engineered mice

Over the past several years, our group has studied the role of tumor stroma in limiting drug delivery and promoting primary chemoresistance in pancreatic ductal adenocarcinoma (PDA). A key player in this process is the Hedgehog (Hh) pathway which forms a paracrine signal to promote desmoplasia. Overexpression of the secreted ligand Sonic Hedgehog begins early in PDA tumorigenesis and acts to promote the proliferation of nearby stromal cells, recapitulating a role of the Hh pathway in mammalian development. By intervening in this axis through pharmacological inhibition with a Smoothened (Smo) inhibitor, we previously demonstrated increased delivery of chemotherapy to tumors arising in a genetically engineered model of PDA, resulting in improved overall survival. However, subsequent clinical trials in metastatic PDA found that those patients treated with chemotherapy + placebo lived longer than those with chemotherapy + Smo inhibitor. To better understand this outcome, we performed a series of “post-clinical trials” in genetically engineered mice. Surprisingly, we found that early and prolonged Smoothened inhibition led to a dramatic acceleration of pancreatic tumorigenesis. This contrasted starkly with our previous findings of prolonged survival using a short treatment course in large, late-stage tumors. Moreover, Smoothened inhibitor treated tumors were poorly differentiated, highly vascularized, and lacking in desmoplastic stroma. During pancreatic development, 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 characteristic of human PDA. To directly test the hypothesis that Smo inhibition and subsequent stromal depletion causes change in differentiation state, we employed a newly developed abdominal laparotomy procedure to acquire pre- and post-treatment tumors samples from mice treated with Smo inhibitor. Data from the first 8 animals evaluated show clear indications of de-differentiation and trans-differentiation. Ongoing molecular and genomic analyses will determine whether this reflects a change in the underlying molecular class of the tumor, and will aid in our understanding of the basic molecular mechanisms responsible for this dramatic alteration in phenotype. Reporter alleles are being utilized to identify the stromal cell types involved in the paracrine Hedgehog signalling axis in PDA. These data will also be informative for our understanding of the many stroma-targeted therapies that are currently undergoing clinical development. This abstract is also presented as Poster B22. Citation Format: Paul E. Oberstein, Dafydd H. Thomas, Carmine F. Palermo, Stephen A. Sastra, Kenneth P. Olive. Paradoxical acceleration of pancreatic tumorigenesis through Smoothened inhibition: A post-clinical trial in genetically engineered mice. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr PR01.