biostudies-literatureRoy Chaudhuri TNational Center for Advancing Translational SciencesCenter for Protein Therapeutics, University at BuffaloNCATS NIH HHSCancer Research UKHealth and Social Care Northern IrelandScience Foundation IrelandMedical Research CouncilRoswell Park Comprehensive Cancer CenterNational Cancer InstituteNCI NIH HHSNew York State Stem Cell ScienceDivision of Chemical, Bioengineering, Environmental, and Transport Systems1367-1381https://www.ebi.ac.uk/biostudies/studies/S-EPMC11019863biostudies-literatureUnknown30(7)<h4>Purpose</h4>Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) "primes" PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on cClinical cancer research : an official journal of the American Association for Cancer ResearchDual-Hit Strategy for Therapeutic Targeting of Pancreatic Cancer in Patient-Derived Xenograft Tumors.PMC11019863P30CA016056C026415R21 CA234775MC_PC_15013UL1TR001412R21CA168454UL1 TR001412R01 CA198096C026714R21 CA168454C11884/A24367R01CA198096CBET-1706050P30 CA016056SFI/14/US/B2997STL/5010/14CBET-1555720R21CA234775Quinn GPLin QScott CJSpernyak JAMa WWStachowiak MKRosario SRMcDade SSGreene MKStachowiak EKStraubinger RMRoy Chaudhuri TClynes MfalseDual-Hit Strategy for Therapeutic Targeting of Pancreatic Cancer in Patient-Derived Xenograft Tumors.<h4>Purpose</h4>Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) "primes" PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on c2024-01-01T00:00:00Z2024 Apr2026-06-02T11:45:53.952Z2025-04-04T12:53:53.281ZS-EPMC110198633827058210.1158/1078-0432.ccr-23-013110.1158/1078-0432.CCR-23-0131