Affatato Roberta, Chiappa Michela, Guffanti Federica, Ricci Francesca, Formenti Laura, Fruscio Robert, Jaconi Marta, Ridinger Maya, Erlander Mark, Damia Giovanna
Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Laboratory of Cancer Metastasis Therapeutics, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Ther Adv Med Oncol. 2022 May 31;14:17588359221095064. doi: 10.1177/17588359221095064. eCollection 2022.
Ovarian carcinoma is extremely sensitive to (platinum-based) chemotherapy; however, most patients will relapse with platinum-resistant disease, badly affecting their prognosis. Effective therapies for relapsing resistant tumors are urgently needed.
We used patient-derived xenografts (PDXs) of ovarian carcinoma resistant to cisplatin (DDP) to test the combination of paclitaxel (15 mg/kg i.v. once a week for 3 weeks) and onvansertib, a plk1 inhibitor, (50 mg/kg orally 4 days a week for 3 weeks). The PDX models were subcutaneously (s.c.) or orthotopically transplanted in nude mice and antitumor efficacy was evaluated as tumor growth inhibition and survival advantages of the combination over untreated and single agent treatment.
The combination of onvansertib and paclitaxel was very well tolerated with weight loss no greater than 15% in the combination group compared with the control group. In the orthotopically transplanted PDXs, single onvansertib and paclitaxel treatments prolonged survival; however, the combined treatment was much more active, with median survival from three- to six-fold times that of untreated mice. Findings were similar with the s.c. transplanted PDX, though there was greater heterogeneity in tumor response. tumors treated with the combination showed greater induction of γH2AX, marker of apoptosis and DNA damage, and pSer10H3, a marker of mitotic block.
The efficacy of onvansertib and paclitaxel combination in these preclinical ovarian cancer models supports the clinical translatability of this combination as an effective therapeutic approach for platinum-resistant high-grade ovarian carcinoma.
卵巢癌对（铂类）化疗极为敏感；然而，大多数患者会复发为铂耐药疾病，严重影响其预后。迫切需要针对复发性耐药肿瘤的有效治疗方法。
我们使用对顺铂（DDP）耐药的卵巢癌患者来源的异种移植瘤（PDXs）来测试紫杉醇（15mg/kg静脉注射，每周一次，共3周）和plk1抑制剂onvansertib（50mg/kg口服，每周4天，共3周）的联合用药效果。将PDX模型皮下（s.c.）或原位移植到裸鼠体内，并将联合用药的抗肿瘤疗效评估为与未治疗和单药治疗相比的肿瘤生长抑制和生存优势。
onvansertib和紫杉醇的联合用药耐受性良好，联合用药组的体重减轻不超过15%，而对照组体重减轻超过15%。在原位移植的PDXs中，单独使用onvansertib和紫杉醇治疗可延长生存期；然而，联合治疗的效果更佳，中位生存期是未治疗小鼠的三至六倍。皮下移植的PDX也有类似的结果，尽管肿瘤反应的异质性更大。联合治疗的肿瘤显示出更多的γH2AX（凋亡和DNA损伤的标志物）和pSer10H3（有丝分裂阻滞的标志物）的诱导。
onvansertib和紫杉醇联合用药在这些临床前卵巢癌模型中的疗效支持了这种联合用药作为铂耐药高级别卵巢癌有效治疗方法的临床可转化性。
