The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases
The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases
复制标题
DOI：
10.1158/1535-7163.mct-21-0420
复制
发表时间：
2022-04-01
影响因子：
5.7
通讯作者：
Bani, Maria Rosa
中科院分区：
文献类型：
--
作者：
Anastasia, Alessia;Dellavedova, Giulia;Bani, Maria Rosa
卵巢癌是最致命的妇科癌症，当疾病扩散到整个腹膜腔时，5 年生存率为 30%。我们研究了 DNA 依赖性蛋白激酶 (DNA-PK) 抑制剂 AZD7648 与两种患者管理治疗方案（聚乙二醇化脂质体阿霉素 (PLD) 或 PARP 抑制剂奥拉帕尼）联合用药延缓疾病进展的功效。将患者来源的卵巢癌异种移植物（OC-PDX）皮下移植以评估治疗对肿瘤生长的影响，或原位移植到腹膜腔以评估对转移扩散的影响。 AZD7648 与 PLD（静脉给药）或奥拉帕尼（口服）联合口服给药。为了证明肿瘤中 DNA-PK 的抑制作用，我们测量了 DNA-PK 活性的生物标志物 pDNA-PKcs、pRPA32 和 'yH2AX。AZD7648 增强了所有测试的 OC-PDX 中 PLD 的治疗效果，无论其 BRCA 状态或对顺铂或 PLD 的敏感性如何。该治疗使疾病稳定下来，尽管皮下生长的肿瘤停止治疗，但疾病仍持续存在，并显着损害了腹部转移扩散，延长了原位植入小鼠的寿命。AZD7648增强了奥拉帕尼在BRCA缺陷的OC-PDX中的疗效，但没有使BRCA熟练的OC-PDX对奥拉帕尼敏感，尽管对DNA-PK有同等的抑制作用，这表明需要预先存在的药物奥拉帕尼活性受益于添加 AZD7648。这项工作表明，DNA-PK 抑制剂 AZD7648 与 PLD 或奥拉帕尼联合给药是一种令人兴奋的治疗选择，可以使卵巢癌患者受益，应该在临床试验中进行探索。
Ovarian cancer is the deadliest gynecologic cancer, with a 5-year survival rate of 30%, when the disease has spread throughout the peritoneal cavity.We investigated the efficacy to delay disease progression by the DNA-dependent protein kinase (DNA-PK) inhibitor AZD7648, administered in combination with two of the therapeutic options for patient management: either pegylated liposomal doxorubicin (PLD) or the PARP inhibitor olaparib. Patient-derived ovarian cancer xenografts (OC-PDX) were transplanted subcutaneously to evaluate the effect of treatment on tumor growth, or orthotopically in the peritoneal cavity to evaluate the effect on metastatic spread. AZD7648 was administered orally in combination with PLD (dosed intravenously) or with olaparib (orally). To prove the inhibition of DNA-PK in the tumors, we measured pDNA-PKcs, pRPA32, and 'yH2AX, biomarkers of DNA-PK activity.AZD7648 enhanced the therapeutic efficacy of PLD in all the OC-PDXs tested, regardless of their BRCA status or sensitivity to cisplatin or PLD. The treatment caused disease stabilization, which persisted despite therapy discontinuation for tumors growing subcutaneously, and significantly impaired the abdominal metastatic dissemination, prolonging the lifespan of mice implanted orthotopically.AZD7648 potentiated the efficacy of olaparib in BRCA-deficient OC-PDXs but did not sensitize BRCA-proficient OC-PDXs to olaparib, despite an equivalent inhibition of DNA-PK, suggesting the need of a preexisting olaparib activity to benefit from the addition of AZD7648.This work suggests that AZD7648, an inhibitor of DNA-PK, dosed in combination with PLD or olaparib is an exciting therapeutic option that could benefit patients with ovarian cancer and should be explored in clinical trials.