Chiang Shannon, Garcia Netto Keilah, Kokkinos John, Haghighi Koroush S, Raina Aparna S, Youkhana Janet, Pitiyarachchi Omali, Truong Quach, Wenholz Daniel, Wilkinson John, Laczka Olivier, Li Xiang, Aldilla Vina R, Kumar Naresh, Goldstein David, Sharbeen George, Phillips Phoebe A
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.
Sci Rep. 2025 Jul 8;15(1):24488. doi: 10.1038/s41598-025-09411-2.
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.
胰腺导管腺癌（PDAC）是一种极具致死性的恶性肿瘤，迫切需要更有效的治疗方法。癌症相关成纤维细胞（CAFs）通过营造阻碍药物的纤维化微环境，促使该疾病具有侵袭性和化疗抗性。我们研发了新型化合物，即外消旋体CRO-05及其活性对映体CRO-67，它们对胰腺肿瘤细胞和CAF细胞均有靶向作用，具有强大的抗癌活性。这些化合物是基于一类抗癌药物苯并二氢吡喃，运用合理药物化学设计而成。在一个模拟该疾病三维复杂性的临床相关患者来源的PDAC肿瘤外植体模型中评估了它们的治疗潜力和疗效。在这些外植体中，CRO-67处理显著降低了肿瘤细胞和αSMA CAF的频率，减少了细胞增殖并增加了细胞死亡。在体外，CRO-67还通过抑制PDAC细胞和患者来源的CAFs中G2/M期的细胞周期进程，显著降低了细胞增殖并增强了细胞凋亡。CRO-67对小鼠原位PDAC肿瘤的治疗显著抑制了活跃生长肿瘤（终点时生长超过150%）的肿瘤生长，并重塑了肿瘤基质（降低αSMA CAF频率、减轻肿瘤纤维化并使肿瘤血管正常化）。最后，CRO-67在体外使PDAC细胞对多种标准护理化疗药物敏感，为未来联合治疗的开发和验证铺平了道路。
