Cancer Metastasis Therapeutics, Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
Bioscience, Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
Cancer Res Commun. 2023 Mar 27;3(3):489-500. doi: 10.1158/2767-9764.CRC-22-0423. eCollection 2023 Mar.
PARP inhibitors (PARPi) have changed the management of patients with ovarian cancer and their effectiveness has been demonstrated especially in homologous recombination repair-deficient tumors. These first-generation drugs target PARP1, but also PARP2 and other family members potentially responsible for adverse effects that limit their therapeutic potential and restrict their use in combination with chemotherapeutic agents. We investigated ovarian cancer patient-derived xenografts (OC-PDXs) to assess whether malignant progression could be impaired by a novel inhibitor selective for PARP1 (AZD5305) and to assess the potential of its combination with carboplatin (CPT), the standard-of-care for patients with ovarian cancer. In -mutated OC-PDXs, AZD5305 achieved greater tumor regressions and longer duration of response as well as a superior impairment of visceral metastasis and improved survival benefit compared with the first-generation dual PARP1/2 inhibitors. The combination of AZD5305 plus CPT was more efficacious than single agents. Subcutaneously growing tumors experienced regression that persisted after therapy stopped. Combination efficacy was greater against tumors that did not respond well to platinum, even at a dose at which AZD5305 monotherapy was ineffective. The combination therapy impaired metastatic dissemination and significantly prolonged the lifespan of mice bearing OC-PDXs in their abdomen. This combination benefit was evident even when CPT was used at suboptimal doses, and was superior to full-dose platinum treatment. These preclinical studies demonstrate that the PARP1-selective inhibitor AZD5305 retains and improves the therapeutic benefit of the first-generation PARPi, providing an opportunity to maximize benefits for this class of anticancer agents.
Selective PARP1i AZD5305 can exceed the efficacy of first-generation PARPi, which target both PARP1 and PARP2, and potentiates the efficacy of CPT when given in combination. AZD5305 alone or in combination with platinum delayed visceral metastasis, ultimately extending the lifespan of OC-PDX-bearing mice. These preclinical models mimic the progression of the disease occurring in patients after debulking surgery, and are translationally relevant.
PARP 抑制剂（PARPi）改变了卵巢癌患者的治疗方法，其疗效尤其在同源重组修复缺陷的肿瘤中得到了证实。这些第一代药物靶向 PARP1，但也靶向 PARP2 和其他家族成员，这些成员可能会产生不良反应，限制了它们的治疗潜力，并限制了它们与化疗药物联合使用。我们研究了卵巢癌患者来源的异种移植瘤（OC-PDXs），以评估新型 PARP1 选择性抑制剂（AZD5305）是否能抑制肿瘤恶性进展，并评估其与卡铂（CPT）联合应用的潜力，CPT 是卵巢癌患者的标准治疗方法。在 - 突变的 OC-PDXs 中，AZD5305 实现了更大的肿瘤消退和更长的缓解时间，以及更好地抑制内脏转移和提高生存获益，与第一代双重 PARP1/2 抑制剂相比。AZD5305 联合 CPT 的疗效优于单药。皮下生长的肿瘤在停止治疗后仍有消退。联合治疗对铂类药物反应不佳的肿瘤更有效，即使在 AZD5305 单药治疗无效的剂量下也是如此。该联合疗法抑制了转移性扩散，并显著延长了携带 OC-PDXs 的小鼠的寿命。即使 CPT 以亚最佳剂量使用，这种联合治疗也能带来益处，并且优于全剂量铂类治疗。这些临床前研究表明，PARP1 选择性抑制剂 AZD5305 保留并提高了第一代 PARPi 的治疗益处，为最大化这一类抗癌药物的益处提供了机会。
选择性 PARP1i AZD5305 可以超过靶向 PARP1 和 PARP2 的第一代 PARPi 的疗效，并在联合使用 CPT 时增强其疗效。AZD5305 单独或与铂类药物联合使用可延迟内脏转移，最终延长携带 OC-PDXs 小鼠的寿命。这些临床前模型模拟了减瘤手术后患者疾病的进展，具有转化相关性。
