Abstract Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer related deaths with 5-year survival rates less than 6%. Survival periods with gemcitabine in combination with various agents average over 6 months. Desmoplasia is a striking feature of pancreatic cancer. It is characterized by formation of dense stroma surrounding the tumor. This dense stroma serves as a therapeutic barrier for many chemotherapeutic drugs, in turn decreasing their efficacy. Pancreatic stellate cells (PSCs) have been reported to be involved in the observed desmoplastic reaction. Therefore targeting this stroma can be an alternate approach to pancreatic cancer. Previous studies from our laboratory showed that Nexrutine, a herbal supplement inhibits proliferation of multiple pancreatic cancer cells through modulation of Stat3/NFκB/Cox-2 signaling and reduced the number of animals developing fibrosis in vivo. To the best of our knowledge, the effect of Nexrutine or its active components on pancreatic stroma has not been studied. In this study we evaluated the effect of Nexrutine and Palmatine, an active component of Nexrutine, for its ability to target the stroma. Our studies show for the first time that Palmatine (i) inhibits proliferation of PSCs as well as the tumor cells; (ii) inhibits hedgehog signaling as evidenced by GLI expression and reporter activity; (iii) modulates expression and activity of downstream targets of GLI including Patched1, IKKB-ε and anti-apoptotic protein Survivin. Remarkably Palmatine treatment inhibits invasive ability of PSCs that is associated with reduced levels of COL1A1. Overall this is the first study reporting the ability of Palmatine to modulate Hh signaling and may have utility either alone or in conjunction with Gemcitabine for treatment of pancreatic ductal adenocarcinoma. Supported by NCCAM (AT 005513-01A1 and AT 007448l; APK). Citation Format: Divya Chakravarthy, Jingjing Gong, Rosa F. Hwang, Addanki Pratap Kumar. Targeting pancreatic cancer stroma with Palmatine, a novel compound from herbal supplement. [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 LB-101. doi:10.1158/1538-7445.AM2013-LB-101