2025
Sci Rep. 2025 Jul 8;15(1):24488. doi: 10.1038/s41598-025-09411-2.
CRO-67 has anti-cancer activity in pancreatic tumor cells and stromal cancer-associated fibroblasts
Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, 2052, Australia. School of Medicine, Sydney Campus, University of Notre Dame Australia, Sydney, NSW, 2007, Australia. Prince of Wales Hospital, School of Clinical Medicine, Randwick Clinical Campus, UNSW Sydney, Sydney, NSW, 2052, Australia. Noxopharm Limited, Sydney, NSW, 2154, Australia. School of Chemistry, UNSW Sydney, Sydney, NSW, 2052, Australia. Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, 2052, Australia. g.sharbeen@unsw.edu.au. Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, 2052, Australia. p.phillips@unsw.edu.au. # Contributed equally.
Service type: Stock strains
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that urgently needs more effective therapies. Cancer-associated fibroblasts (CAFs) contribute to the aggressive and chemo-resistant nature of the disease by creating a drug-impeding fibrotic microenvironment. We developed novel compounds, the racemate CRO-05 and its active enantiomer CRO-67, which target both pancreatic tumor and CAF cells with robust anti-cancer activity. These compounds were designed using rational medicinal chemistry based on chromans, a class of anti-cancer drugs. Their therapeutic potential and efficacy were assessed in a clinically relevant patient-derived PDAC tumor explant model, which mimics the disease's 3-dimensional complexity. CRO-67 treatment in these explants significantly reduced tumor cell and αSMA+ CAF frequency, decreased cell proliferation and increased cell death. CRO-67 also significantly decreased cell proliferation and enhanced apoptosis by inhibiting cell cycle progression through G2/M phase in PDAC cells and patient-derived CAFs in vitro. CRO-67 treatment of orthotopic PDAC tumors in mice significantly reduced tumor growth in tumors with active growth (> 150% growth at endpoint), and remodeled tumor stroma (reduced αSMA+ CAF frequency, loosened tumor fibrosis and normalized tumor vasculature). Finally, CRO-67 sensitized PDAC cells to multiple standard-of-care chemotherapeutics in vitro, paving the way for future combination therapy development and validation. Keywords: CRO-67; Cancer-associated fibroblast; Pancreatic cancer; Stromal reprogramming.
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