Washington University PDX Development and Trial Center - Evaluation of Abemaciclib in Combination with Olaparib in Ovarian Cancer and Breast Cancer Patient-derived Xenograft Models

华盛顿大学 PDX 开发和试验中心 - Abemaciclib 联合 Olaparib 在卵巢癌和乳腺癌患者异种移植模型中的评估

• 批准号: 10582164
• 负责人: Li Ding
• 金额: $ 20万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582164
• 关键词: Apoptosis; Biological; Biological Markers; Biology; Breast Cancer Model; Breast Cancer cell line; CCNE1 gene; CDK4 gene; Cancer Model; Cancer Therapy Evaluation Program; Cells; Clinical Trials; Clinical Trials Network; Collaborations; Cyclin-Dependent Kinases; DNA Damage; DNA Repair Gene; Data; Data Set; Development; Disease; Drug Administration Schedule; Drug Interactions; Drug Kinetics; Effectiveness; Evaluation; Exposure to; G1 Arrest; G1/S Checkpoint Pathway; G2 Phase; Gene Expression; Genetic; Goals; Investigational Therapies; Malignant neoplasm of ovary; Mediating; Medical; Modeling; Mutate; Neuroendocrine Prostate Cancer; Patient-derived xenograft models of breast cancer; Pharmaceutical Preparations; Pharmacodynamics; Phosphotransferases; Plasma; Poly(ADP-ribose) Polymerases; S phase; Schedule; Sequential Treatment; Serous; Universities; Washington; Xenograft procedure; biomarker-driven; combinatorial; comparative efficacy; cytotoxic; cytotoxicity; experimental study; gene induction; homologous recombination; in vivo; inhibitor; interest; malignant breast neoplasm; overexpression; patient derived xenograft model; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; phase 1 study; pre-clinical; recombinational repair; response; retinoblastoma pathway; synergism; treatment center; triple-negative invasive breast carcinoma; tumor

PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-22-039. Recent studies have demonstrated synergism of combined poly (ADP-ribose) polymerase (PARP) and selective cyclin-dependent kinase (CDK)4/6 inhibition in high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) cell lines, prompting the development of an NCI-CTEP- sponsored combination clinical trial of the PARP inhibitor olaparib and the CDK4/6 inhibitor abemaciclib. However, synergism is context-dependent and appears to occur in a background of MYC amplification or overexpression. In the absence of high levels of MYC, the G1 arrest afforded by a CDK4/6 inhibitor may antagonize PARP inhibitor-mediated cytotoxicity, which occurs during S phase. In contrast, high MYC expression may overcome CDK4/6 inhibitor-induced G1 arrest; CDK4/6 inhibition during the S and G2 phases may reduce expression of DNA repair genes, including those involved in homologous recombination (HR) repair, facilitating sensitization to PARP inhibition. Similar biology may also operate in cells expressing high levels of cyclin E. In cells with high MYC or cyclin E, concomitant exposure may produce cytotoxic synergism; however, in cells without a high degree of MYC or cyclin E expression, a sequential schedule may be required, in which olaparib precedes abemaciclib. To develop in vivo data supporting the ongoing clinical trial, we have established a Patient Derived Xenograft (PDX) Development and Treatment Center–Experimental Therapeutics Clinical Trials Network (ETCTN) collaboration to study the combination of olaparib and abemaciclib in HGSOC and TNBC PDX models. In the first Specific Aim, we will evaluate 6 models with high MYC and/or CCNE1 amplification to assess efficacy of concomitant olaparib/abemaciclib exposure compared to monotherapies. We will evaluate biomarkers of G1 arrest, reduced HR gene expression, DNA damage and apoptosis. Efficacy and pharmacodynamic endpoints will be correlated with plasma and intratumoral pharmacokinetic assessments, to evaluate potential drug-drug interactions and to establish drug concentrations required for antitumor activity and biological effectiveness. In the second Specific Aim, similar experiments will be conducted with HGSOC and TNBC PDX models that do not express high levels of MYC or cyclin E, where concomitant and sequential administration schedules will be compared, along with similar pharmacodynamic and pharmacokinetic assessments. The data derived through this collaborative effort will establish the mechanism of synergism for the combination and provide a biomarker-driven approach to the scheduling of drug administration.

项目摘要/摘要 本申请是为了响应特别利益通知（NOSI）而提交的，该通知被确定为 NOT-CA-22-039。最近的研究表明，联合聚（ADP-核糖）聚合酶的协同作用 PARP和选择性细胞周期蛋白依赖性激酶（CDK）4/6抑制在高级别浆液性卵巢癌中的作用 （HGSOC）和三阴性乳腺癌（TNBC）细胞系，促进了NCI-CTEP- PARP抑制剂奥拉帕尼和CDK 4/6抑制剂abemaciclib的联合临床试验。 然而，协同作用是上下文依赖性的，并且似乎发生在MYC扩增的背景下，或者 过度表达在没有高水平MYC的情况下，CDK 4/6抑制剂提供的G1期阻滞可能 拮抗PARP介导的细胞毒性，其发生在S期。相比之下，高MYC 表达可以克服CDK 4/6介导的G1期阻滞;在S期和G2期CDK 4/6抑制 可能减少DNA修复基因的表达，包括参与同源重组（HR）修复的基因， 促进对PARP抑制的敏感性。类似的生物学也可以在表达高水平的 细胞周期蛋白E。在具有高MYC或细胞周期蛋白E的细胞中，伴随暴露可能产生细胞毒性协同作用;然而， 在没有高度MYC或细胞周期蛋白E表达的细胞中，可能需要顺序方案，其中 奥拉帕尼先于abemaciclib。为了开发支持正在进行的临床试验的体内数据，我们建立了 患者源性异种移植（PDX）开发和治疗中心-实验治疗学临床 试验网络（ETCTN）合作研究奥拉帕尼和abemaciclib联合治疗HGSOC和TNBC PDX模型。在第一个特定目标中，我们将评估6个具有高MYC和/或CCNE 1扩增的模型， 评估与单药治疗相比，奥拉帕尼/玻玛西尼合并暴露的疗效。我们将评估 G1期阻滞、HR基因表达减少、DNA损伤和细胞凋亡的生物标志物。疗效和 药效学终点将与血浆和肿瘤内药代动力学评估相关， 评价潜在的药物相互作用，并确定抗肿瘤活性所需的药物浓度， 生物效能。在第二个具体目标中，将对HGSOC进行类似的实验， 不表达高水平MYC或细胞周期蛋白E的TNBC PDX模型，其中伴随和顺序 将比较给药方案，沿着相似的药效学和药代动力学 评估。通过这一合作努力获得的数据将建立协同作用机制， 该组合提供了生物标志物驱动的药物给药时间安排方法。