The MSKCC-UW/Fred Hutch Prostate Cancer Drug Resistance and Sensitivity Center

总体摘要 转移性前列腺癌的致命阶段，称为去势抵抗性前列腺癌（CRPC）， 美国每年约有26，000人。尽管下一代AR的生存率有了显着提高， 途径抑制剂（如阿比特龙和恩杂鲁胺），CRPC患者最终会病情进展并死亡 他们的疾病。我们对AR治疗获得性耐药机制的理解有所增加， 近年来，这在很大程度上是基于CRPC患者肿瘤的基因组景观分析， 在患者衍生模型（类器官，PDX）中进行获得性耐药性的临床前研究。这一进展的大部分是 直接联系到这个耐药性和敏感性中心（DRSC）团队的成员。一个主要 这些研究的机制性见解是认识到两类AR治疗抵抗：一类是AR治疗抵抗。 其中AR通路信号传导被恢复，而另一个通路信号传导仍然被抑制。这两个类别的基础 是一组异质的耐药机制，其中许多是由我们的DRSC团队发现的 成员重要的是，我们已经证明，这些耐药机制中的几种可以通过 目前的临床药物。本DRSC提案的总体目标是评估这些翻译 在一组独特的临床前类器官和PDX模型中的机会（同样，由 我们的DRSC团队成员），并促进在最有可能受益的患者中启动临床研究 基于适当的生物标志物图谱。我们在三个项目中实现这一目标。项目1的重点是 AR通路功能恢复引起的抵抗，超过50%的CRPC患者发生这种情况， 糖皮质激素受体，其被上调并替代AR，或通过进一步抑制AR信号传导 使用针对染色质机器特定成分的药物。项目2将采取类似的方法 但将集中于获得性抗性的相反类别（缺乏恢复的AR途径活性）， 利用我们最近的数据显示癌症可以从AR阴性逆转为AR阳性的见解， 通过靶向特定的染色质修饰剂。项目3与项目1和项目2相结合， 激酶抑制剂在两种不同情况下作为AR途径治疗的辅助药物-肿瘤中的PI 3 K/AKT活化 在具有自分泌FGF 8/FGF 9产生的肿瘤中具有PTEN损失和FGFR活化。令人兴奋的是，最近 基于我们早期的工作启动的AKT和AR联合抑制的临床试验表明， PTEN缺失前列腺癌患者的生存率显著提高。行政核心将 监督各项目之间、与NCI科学工作人员之间以及与其他DRSC之间的整合。 总体而言，我们的研究将验证各种联合治疗方案，结合分子生物学， 生物标志物用于患者选择，作为临床转化的关键一步。此外，药物和靶点 这些研究与多种癌症类型广泛相关。

OVERALL ABSTRACT The lethal stage of metastatic prostate cancer, called castration resistant prostate cancer (CRPC), kills ~26,000 men per year in the US. Despite remarkable improvements in survival with next generation AR pathway inhibitors such as abiraterone and enzalutamide, CRPC patients ultimately progress and die from their disease. Our understanding of the mechanisms of acquired resistance to AR therapy has increased dramatically in recent years, largely based on genomic landscape analyses of tumors from CRPC patients and preclinical studies of acquired resistance in patient-derived models (organoids, PDX). Much of this progress is directly linked to the members of this Drug Resistance and Sensitivity Center (DRSC) team. A major mechanistic insight from these studies is the recognition of two categories of AR therapy resistance: one in which AR pathway signaling is restored and the other in which it remains inhibited. Underlying both categories are a heterogeneous set of resistance mechanisms, many of which were discovered by our DRSC team members. Importantly, we have shown that several of these resistance mechanisms can be targeted with current clinical grade drugs. The overarching goal of this DRSC proposal is to evaluate these translational opportunities across a unique set of preclinical organoid and PDX models (again, discovered and developed by our DRSC team members) and to catalyze the initiation of clinical studies in patients most likely to benefit based on appropriate biomarker profiles. We address this goal in three Projects. Project 1 focuses on resistance caused by restored AR pathway function, which occurs in over ~50% of CRPC patients, by targeting the glucocorticoid receptor, which is upregulated and substitutes for AR, or by further inhibition of AR signaling using drugs targeting specific components of the chromatin machinery. Project 2 will take a similar approach but will focus on the opposite category of acquired resistance (absence of restored AR pathway activity), leveraging insights from our recent data showing that cancer can revert from an AR-negative to AR-positive state by targeting specific chromatin modifiers. Project 3 integrates with Projects 1 and 2 by focusing on kinase inhibitors as an adjunct to AR pathway therapy in two distinct contexts – PI3K/AKT activation in tumors with PTEN loss and FGFR activation in tumors with autocrine FGF8/FGF9 production. Excitingly, a recent clinical trial of combined AKT and AR inhibition, which was initiated based on our earlier work, demonstrated a significant improvement in survival for patients with PTEN loss prostate cancer. The Administrative Core will oversee the integration of the Projects with each other, with NCI scientific staff and with other DRSCs. Collectively our studies will validate various combination therapy regimens, in conjunction with molecular biomarkers for patient selection, as a critical step toward clinical translation. In addition, the drugs and targets studied here are broadly relevant for multiple cancer types.