Roze Joline, Sendino Garví Elena, Stelloo Ellen, Stangl Christina, Sereno Ferdinando, Duran Karen, Groeneweg Jolijn, Paijens Sterre, Nijman Hans, van Meurs Hannah, van Lonkhuijzen Luc, Piek Jurgen, Lok Christianne, Jonges Geertruida, Witteveen Petronella, Verheijen René, van Haaften Gijs, Zweemer Ronald, Monroe Glen
Department of Gynaecological Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands.
Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Oncode Institute, Utrecht University, 3584 CX Utrecht, The Netherlands.
Cancers (Basel). 2021 Jan 20;13(3):368. doi: 10.3390/cancers13030368.
Adult granulosa cell tumors (AGCTs) arise from the estrogen-producing granulosa cells. Treatment of recurrence remains a clinical challenge, as systemic anti-hormonal treatment or chemotherapy is only effective in selected patients. We established a method to rapidly screen for drug responses in vitro using direct patient-derived cell lines in order to optimize treatment selection. The response to 11 monotherapies and 12 combination therapies, including chemotherapeutic, anti-hormonal, and targeted agents, were tested in 12 AGCT-patient-derived cell lines and an AGCT cell line (KGN). Drug screens were performed within 3 weeks after tissue collection by measurement of cell viability 72 h after drug application. The potential synergy of drug combinations was assessed. The human maximum drug plasma concentration (Cmax) and steady state (Css) thresholds obtained from available phase I/II clinical trials were used to predict potential toxicity in patients. Patient-derived AGCT cell lines demonstrated resistance to all monotherapies. All cell lines showed synergistic growth inhibition by combination treatment with carboplatin, paclitaxel, and alpelisib at a concentration needed to obtain 50% cell death (IC50) that are below the maximum achievable concentration in patients (IC50 < Cmax). We show that AGCT cell lines can be rapidly established and used for patient-specific in vitro drug testing, which may guide treatment decisions. Combination treatment with carboplatin, paclitaxel, and alpelisib was consistently effective in AGCT cell lines and should be further studied as a potential effective combination for AGCT treatment in patients.
成人颗粒细胞瘤（AGCTs）起源于产生雌激素的颗粒细胞。复发的治疗仍然是一项临床挑战，因为全身抗激素治疗或化疗仅对部分患者有效。我们建立了一种方法，利用直接来自患者的细胞系在体外快速筛选药物反应，以优化治疗选择。在12个源自AGCT患者的细胞系和1个AGCT细胞系（KGN）中测试了对11种单一疗法和12种联合疗法的反应，这些疗法包括化疗药物、抗激素药物和靶向药物。在组织采集后3周内进行药物筛选，通过测量药物应用72小时后的细胞活力来进行。评估了药物组合的潜在协同作用。利用从现有的I/II期临床试验中获得的人体最大药物血浆浓度（Cmax）和稳态（Css）阈值来预测患者的潜在毒性。源自患者的AGCT细胞系对所有单一疗法均表现出耐药性。所有细胞系在与卡铂、紫杉醇和阿培利司以获得50%细胞死亡所需浓度（IC50）联合治疗时均表现出协同生长抑制，该浓度低于患者可达到的最大浓度（IC50 < Cmax）。我们表明，可以快速建立AGCT细胞系并将其用于针对患者的体外药物测试，这可能会指导治疗决策。卡铂、紫杉醇和阿培利司联合治疗在AGCT细胞系中始终有效，应作为AGCT患者潜在的有效联合治疗进一步研究。
