Guffanti Federica, Mengoli Ilaria, Ricci Francesca, Perotti Ludovica, Capellini Elena, Sala Laura, Canesi Simone, Wu Chu-Chiao, Fruscio Robert, Ridinger Maya, Damia Giovanna, Chiappa Michela
Laboratory of Gynecological Preclinical Oncology, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy.
Mouse & Animal Pathology Laboratory (MAPLab), Fondazione UniMi, 20139 Milano, Italy.
Int J Mol Sci. 2025 Jun 14;26(12):5708. doi: 10.3390/ijms26125708.
Platinum resistance represents an urgent medical need in the management of ovarian cancer. The activity of the combinations of onvansertib, an inhibitor of polo-like kinase 1, with gemcitabine or carboplatin was tested using patient-derived xenografts of high-grade serous ovarian carcinoma resistant to cisplatin (DDP). Two PDX models were selected from our xenobank: one with acquired resistance to DDP (#266R) and the other (#315) with intrinsic DDP resistance. Tumor-bearing mice were randomized to receive vehicle, single onvansertib, gemcitabine and carboplatin, and their combinations. Onvansertib/gemcitabine and onvansertib/carboplatin combinations were well tolerated. In the #266R model, single drug treatments were completely inactive, while the combinations of onvansertib/gemcitabine and onvansertib/carboplatin resulted in a significant increase in survival compared to controls and single drugs ( < 0.001 versus control, onvansertib, gemcitabine and carboplatin). Similar efficacy was observed in the s.c. #315 PDX model; indeed, onvansertib and carboplatin monotherapies were inactive, gemcitabine monotherapy was marginally active, while both combinations were highly active. The molecular mechanism underlying the efficacy of the combinations suggests a higher induction of DNA damage which seems plausible considering that, in both cases, gemcitabine and carboplatin, respectively, interfere with DNA metabolism and induce alkylation damage. The results suggest that the combinations of onvansertib/gemcitabine and onvansertib/carboplatin are safe and were shown to be of therapeutic value in the platinum-resistant setting of ovarian carcinoma, strongly supporting their clinical translatability.
铂类耐药在卵巢癌治疗中是一个亟待解决的医学问题。使用对顺铂（DDP）耐药的高级别浆液性卵巢癌患者来源的异种移植模型，测试了polo样激酶1抑制剂onvansertib与吉西他滨或卡铂联合用药的活性。从我们的异种移植库中选择了两个PDX模型：一个对DDP获得性耐药（#266R），另一个（#315）对DDP具有固有耐药性。将荷瘤小鼠随机分为接受溶剂、单药onvansertib、吉西他滨和卡铂及其联合用药组。Onvansertib/吉西他滨和onvansertib/卡铂联合用药耐受性良好。在#266R模型中，单药治疗完全无效，而onvansertib/吉西他滨和onvansertib/卡铂联合用药与对照组和单药相比，显著提高了生存率（与对照组、onvansertib、吉西他滨和卡铂相比，P<0.001）。在皮下#315 PDX模型中观察到了类似的疗效；实际上，onvansertib和卡铂单药治疗无效，吉西他滨单药治疗有轻微活性，而两种联合用药均具有高活性。联合用药疗效的分子机制表明，DNA损伤诱导更高，考虑到在这两种情况下，吉西他滨和卡铂分别干扰DNA代谢并诱导烷基化损伤，这似乎是合理的。结果表明，onvansertib/吉西他滨和onvansertib/卡铂联合用药是安全的，并且在卵巢癌铂类耐药的情况下具有治疗价值，有力地支持了它们的临床可转化性。
