Kenny Hilary A, Ip Carman Ka Man, Kelliher Lucy, Samantaray Tejas, Kordylewicz Kasjusz, Hoffmann Rachael, Rauch Sarah, Malacrida Beatrice, Skingsley Sophie L P, Balkwill Frances R, Battistini Chiara, Cavallaro Ugo, Wiedemeyer Wolf R, Lengyel Ernst
Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, Illinois.
Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Mol Cancer Ther. 2025 Aug 1;24(8):1252-1264. doi: 10.1158/1535-7163.MCT-23-0863.
High-grade serous ovarian cancer is generally treated with upfront chemotherapy, including carboplatin. The persistence of platinum-resistant cells drives recurrent disease. A high-throughput screen using a 3D organotypic culture assembled with extracellular matrix, primary human fibroblasts, and mesothelial cells was established and validated. Using a library of FDA-approved drugs, the 3D high-throughput screen was performed with the goal of identifying a combination of drugs that synergistically target two populations of ovarian cancer: aldehyde dehydrogenase (ALDH) high (ALDHhi) and ALDH low (ALDHlo) enzyme activity cells, which are less sensitive to carboplatin treatment than the bulk ovarian cancer cells. Initial results showed that omipalisib, verteporfin, CA3, mitoxantrone, navitoclax, venetoclax, and YM155 had significant single-drug activity in either the ALDHlo or both the ALDHlo/ALDHhi cell populations. Synergistic drug activity was identified with three drug combinations: navitoclax/omipalisib, navitoclax/YM155, and YM155/omipalisib. In vitro, the combination of navitoclax/YM155 was most efficient at blocking primary human ovarian cancer sphere formation and the proliferation of four different ovarian cancer cell lines in the 3D organotypic culture. In vivo, the combination of navitoclax/YM155/carboplatin decreased ovarian cancer metastasis, decreased the percentage of ALDHhi ovarian cancer cells in tumors, and increased survival when compared with carboplatin treatment alone in xenograft models. Our results suggest that the combination of navitoclax/YM155/carboplatin has promise as a therapy for treating ovarian cancer.
高级别浆液性卵巢癌通常采用包括卡铂在内的一线化疗进行治疗。铂耐药细胞的持续存在导致疾病复发。建立并验证了一种使用由细胞外基质、原代人成纤维细胞和间皮细胞组装而成的3D器官型培养物的高通量筛选方法。使用美国食品药品监督管理局（FDA）批准的药物库进行3D高通量筛选，目的是确定一种联合用药方案，该方案能协同靶向两类对卡铂治疗敏感性低于大多数卵巢癌细胞的卵巢癌细胞：醛脱氢酶（ALDH）高活性（ALDHhi）和ALDH低活性（ALDHlo）细胞。初步结果显示，奥米帕利、维替泊芬、CA3、米托蒽醌、维奈托克、纳维托克司和YM155在ALDHlo细胞群体或ALDHlo/ALDHhi细胞群体中均具有显著的单药活性。确定了三种联合用药具有协同活性：纳维托克司/奥米帕利、纳维托克司/YM155和YM155/奥米帕利。在体外，纳维托克司/YM155组合在3D器官型培养中最有效地阻断了原代人卵巢癌球体形成以及四种不同卵巢癌细胞系的增殖。在体内，与异种移植模型中单独使用卡铂治疗相比，纳维托克司/YM155/卡铂组合减少了卵巢癌转移，降低了肿瘤中ALDHhi卵巢癌细胞的百分比，并提高了生存率。我们的结果表明，纳维托克司/YM155/卡铂组合有望成为治疗卵巢癌的一种疗法。
