REPURPOSING THE FDA APPROVED DRUG PYRVINIUM PAMOATE TO TARGET HUR IN PANCREATIC DUCTAL ADENOCARCINOMA
Christopher Schultz1, Teena Dhir*1, Alex Haber1, Wei Jiang1, Saswati N. Chand1, Brown Samantha1, Emanuel Petricoin2, Charles J. Yeo1, Jonathan R. Brody1
1Surgery, Thomas Jefferson University, Philadelphia, PA; 2University of Arizona, Tucson, AZ
Pancreatic ductal adenocarcinoma (PDA) remains a lethal cancer with overall five year survival rates at only 9%. Therefore, there is a dire need for new targeted therapeutics in PDA. HuR (ELAVL1) is an RNA binding protein that upon exposure to intrinsic (low glucose, hypoxia) and extrinsic (chemotherapeutics) stressors translocates from the nucleus to the cytoplasm and binds to a network of pro-survival mRNAs leading to an increase in their stability and translation. HuR is a driver of chemoresistance in PDA and thus a prime target for re-sensitizing PDA cells to current therapies.
Pyrvinium Pamoate (PP) was approved by the FDA to treat pinworms. We have demonstrated that PP inhibits HuR translocation in PDA cell lines using immunofluorescence (IF) and Western Blotting. By inhibiting translocation PP functionally inhibits HuR binding to target mRNA as demonstrated utilizing RNA immunoprecipitation assays. We have found this HuR inhibition is likely through phosphorylation changes in key HuR effectors as shown through phosphoproteomic screening and Western Blotting. Most chemotherapeutics are most effective when used in combination regimens. In order to determine drugs that PP was likely to synergize with we developed isogenic HuR CRISPR knockout cell lines as we had demonstrated that PP is an HuR inhibitor. We tested these cell lines with commonly used pancreatic cancer drugs, and several targeted therapeutics. We found that HuR knockout cells had significant increases in sensitivity upon treatment with oxaliplatin, olaparib, paclitaxel, gemcitabine, 5-fluorouracil, abemaciclib, palbociclib and irinotican. We thus expected and then demonstrated that PP as an HuR inhibitor can synergize with various therapeutics in vitro.
Lastly, in a small pilot experiment, we show that intraperitoneal administration of PP can inhibit PDA cell growth in vivo. We are currently performing pharmacokinetic studies and larger mouse experiments to determine the bioavailability and efficacy of oral PP. We are also working to test drug combination regimens in vitro and in vivo as well. Reconfirming the relevance of targeting HuR in PDA utilizing a tumor microarray, we found that 79% (n=80) of tumors were positive for cytoplasmic HuR, with no cytoplasmic localization detected in adjacent normal tissues. Based on these data, we are in the progress of setting up a clinical trial to determine the safety and bioavailability of PP in PDA cancer patients. In summation we have demonstrated that PP is extremely effective at inhibiting PDA cells in vitro and in vivo, and furthermore that it may be a clinically relevant new therapeutic targeting HuR in PDA.
Initial pilot experiments demonstrated a considerable reduction in tumor growth when treated IP at 1mg/kg, when compared to no treatment. 
Repeat in vivo experiment comparing IP PP dosing to oral PP dosing at 3 different concentrations. Graph is plotting average tumor volume in each group at 15 days into the experiment.
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