LAUSR

We have demonstrated that 3DNA nanocarriers can specifically, effectively, and safely deliver siRNA oligos targeted against a pro-survival hub, HuR (the ELAVL1 gene) in an in vivo, pre-clinical model of pancreatic cancer. Pancreatic cancer remains one of the deadliest cancers with an overall 5 year survival rate of 9%; and is on pace to become the second leading cause of cancer related deaths in the U.S. by 2020. Pancreatic cancer is so deadly, in part, because it is highly refractory to standard chemotherapeutics. In fact, new standard of care regiments such as FOLFIRINOX have only improved survival by a few months. Our previous work has established HuR as a target in pancreatic cancer. HuR is an RNA binding protein that is primarily retained in the nucleus, but upon exposure to cancer associated stressors translocates to the cytoplasm. In the cytoplasm, HuR functions to bind, stabilize, and up-regulate expression of pro-survival target mRNAs. CRISPR-mediated deletion of HuR causes a xenograft lethal phenotype in vivo and increases sensitivity to a variety of drugs, particularly PARP inhibitor therapy, enhancing Olaparib therapy over 20-fold in vitro. In an independent doxycycline inducible knockdown model, HuR depletion combined with Olaparib treatment resulted in a 9.3 fold (p Citation Format: Chris W. Schultz, Kevin O9Hayer, Kathryn M. Bormes, Teena Dhir, Samantha Brown, Avinoam Nevlar, Saswati Chand, Henry Thomsett, Wei Jiang, Jessica Bowers, Kelly Rhodes, Michael Pishvaian, Robert Getts, Jonathan Brody. Re-sensitizing Pancreatic Cancer, targeted siRNA inhibition of HuR [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B19.