Pancreatic ductal adenocarcinoma (PDAC) occurs in the context of an exuberant desmoplastic response that produces a ‘living chimera’ of tumor and activated stromal components. A prominent feature of the stromal response is the transformation of the Vitamin A storing pancreatic stellate cell (PSC) to activated myofibroblasts. We hypothesized that restoration of the quiescent PSC phenotype could disrupt tumor-stroma crosstalk and thus improve response to chemotherapy. Recently, we have shown that the vitamin D receptor (VDR) is expressed at high levels in activated human pancreatic tumor stroma and, in response to ligand, acts as a master transcriptional regulator of PSCs to reprise the quiescent state. In vivo, a synthetic VDR agonist (Cal) induced signal-dependent transcriptional remodeling of tumor stroma, enhancing the anti-tumor effects of gemcitabine by increasing intra-tumoral concentration 5-fold to reduce tumor growth. A survival study in KPC mice shows that addition of CAL results in a 57% increase in lifespan relative to Gemcitabine treatment alone. An approved IND enables the exploration of CAL in the neo-adjuvant setting in patients with resectable PDAC. This Phase I trial is designed to establish whether CAL (Zemplar) is able to reach the tumor and alter genes and other measurable responses linked to stromal reprogramming.
Citation Format: Ronald M. Evans. Pancreatic tumor stroma as a therapeutic target. [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 RAOS15-03. doi:10.1158/1538-7445.AM2015-RAOS15-03