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，称为去势抵抗前列腺癌(CRPC)，可导致死亡 在美国，每年约有2.6万名男性。尽管下一代AR显著提高了存活率 途径抑制剂，如阿比特龙和苯扎鲁胺，CRPC患者最终进展和死亡 他们的病。我们对AR治疗获得性耐药机制的理解有所增加 近年来，很大程度上是基于对CRPC患者和 患者衍生模型(有机化合物，PDX)获得性耐药性的临床前研究。这些进展很大程度上是 直接链接到该耐药和敏感中心(DrSc)团队的成员。一位少校 这些研究的机制洞察是对两类AR治疗抵抗的认识：一种是 其中一个AR通路信号被恢复，而另一个AR通路信号仍然被抑制。在这两个类别下 是一套不同的耐药机制，其中许多是我们的DrSc团队发现的 会员。重要的是，我们已经证明，这些抗性机制中的几种可以作为靶点 当前临床级别的药物。本博士论文提案的首要目标是评估这些翻译版本 一套独特的临床前器官和PDX模型的机会(同样，由 我们的DrSc团队成员)，并催化启动对最有可能受益的患者的临床研究 基于适当的生物标志物轮廓。我们在三个项目中解决了这一目标。项目1的重点是 靶向AR通路功能恢复引起的抵抗，超过50%的CRPC患者会发生这种情况 糖皮质激素受体，它被上调并替代AR，或通过进一步抑制AR信号 使用针对染色质机械的特定组件的药物。项目2将采取类似的方法 但将专注于相反类别的获得性抵抗(缺乏恢复的AR途径活性)， 利用我们最近数据的洞察力表明癌症可以从AR阴性恢复到AR阳性 通过靶向特定的染色质修饰物来控制状态。项目3与项目1和项目2集成，重点是 在两种不同的背景下，作为AR途径治疗的辅助手段的激酶抑制剂--肿瘤中PI3K/AKT的激活 在自分泌FGF8/FGF9产生的肿瘤中，PTEN缺失，FGFR激活。令人兴奋的是，最近的一次 AKT和AR联合抑制的临床试验是在我们早期工作的基础上启动的，显示了一种 PTEN缺失的前列腺癌患者的存活率显著提高。行政核心意志 监督项目之间、与NCI科研人员以及与其他DRSC的整合。 总的来说，我们的研究将验证各种联合治疗方案，结合分子 患者选择的生物标记物，作为临床转化的关键一步。此外，这些药物和靶点 在这里研究的是广泛相关的多种癌症类型。

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.