Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia; Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Melbourne Urological Research Alliance (MURAL), Melbourne, VIC, Australia.
Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
Eur Urol. 2018 Nov;74(5):562-572. doi: 10.1016/j.eururo.2018.06.020. Epub 2018 Jul 23.
The intractability of castration-resistant prostate cancer (CRPC) is exacerbated by tumour heterogeneity, including diverse alterations to the androgen receptor (AR) axis and AR-independent phenotypes. The availability of additional models encompassing this heterogeneity would facilitate the identification of more effective therapies for CRPC.
To discover therapeutic strategies by exploiting patient-derived models that exemplify the heterogeneity of CRPC.
DESIGN, SETTING, AND PARTICIPANTS: Four new patient-derived xenografts (PDXs) were established from independent metastases of two patients and characterised using integrative genomics. A panel of rationally selected drugs was tested using an innovative ex vivo PDX culture system.
The following drugs were evaluated: AR signalling inhibitors (enzalutamide and galeterone), a PARP inhibitor (talazoparib), a chemotherapeutic (cisplatin), a CDK4/6 inhibitor (ribociclib), bromodomain and extraterminal (BET) protein inhibitors (iBET151 and JQ1), and inhibitors of ribosome biogenesis/function (RNA polymerase I inhibitor CX-5461 and pan-PIM kinase inhibitor CX-6258).
Drug efficacy in ex vivo cultures of PDX tissues was evaluated using immunohistochemistry for Ki67 and cleaved caspase-3 levels. Candidate drugs were also tested for antitumour efficacy in vivo, with tumour volume being the primary endpoint. Two-tailed t tests were used to compare drug and control treatments.
Integrative genomics revealed that the new PDXs exhibited heterogeneous mechanisms of resistance, including known and novel AR mutations, genomic structural rearrangements of the AR gene, and a neuroendocrine-like AR-null phenotype. Despite their heterogeneity, all models were sensitive to the combination of ribosome-targeting agents CX-5461 and CX-6258.
This study demonstrates that ribosome-targeting drugs may be effective against diverse CRPC subtypes including AR-null disease, and highlights the potential of contemporary patient-derived models to prioritise treatment strategies for clinical translation.
Diverse types of therapy-resistant prostate cancers are sensitive to a new combination of drugs that inhibit protein synthesis pathways in cancer cells.
去势抵抗性前列腺癌（CRPC）的难治性因肿瘤异质性而加剧，包括雄激素受体（AR）轴的多种改变和 AR 非依赖性表型。获得包含这种异质性的额外模型将有助于为 CRPC 确定更有效的治疗方法。
通过利用代表 CRPC 异质性的患者衍生模型来发现治疗策略。
设计、设置和参与者：从两名患者的独立转移灶中建立了四个新的患者衍生异种移植物（PDX），并通过整合基因组学进行了表征。使用创新的 PDX 体外培养系统测试了一组经过合理选择的药物。
评估了以下药物：AR 信号抑制剂（恩扎卢胺和加特罗尼）、PARP 抑制剂（他拉唑帕尼）、化疗药物（顺铂）、CDK4/6 抑制剂（瑞波西利）、溴结构域和末端（BET）蛋白抑制剂（iBET151 和 JQ1）和核糖体生物发生/功能抑制剂（RNA 聚合酶 I 抑制剂 CX-5461 和泛 PIM 激酶抑制剂 CX-6258）。
使用 Ki67 和 cleaved caspase-3 水平的免疫组织化学评估 PDX 组织体外培养中的药物疗效。还在体内测试了候选药物的抗肿瘤疗效，肿瘤体积是主要终点。使用双尾 t 检验比较药物和对照治疗。
整合基因组学显示，新的 PDX 表现出不同的耐药机制，包括已知和新的 AR 突变、AR 基因的基因组结构重排和神经内分泌样 AR 缺失表型。尽管存在异质性，但所有模型对核糖体靶向药物 CX-5461 和 CX-6258 的组合均敏感。
本研究表明，核糖体靶向药物可能对包括 AR 缺失疾病在内的多种 CRPC 亚型有效，并强调了当代患者衍生模型在为临床转化确定治疗策略方面的潜力。
不同类型的治疗耐药性前列腺癌对一种新的抑制癌细胞蛋白质合成途径的药物组合敏感。
