Identification of therapeutic vulnerabilities in prostate cancer bone metastasis

项目摘要/摘要 前列腺癌的致命性主要是由于转移，转移最常发生在骨骼和 与高发病率相关。尽管最近取得了进展，但目前的治疗方法并不能治愈，因此是新的 迫切需要治疗策略。考虑到转移进展和治疗耐药 发生在整个有机体的背景下，并受到肿瘤微环境的影响，一个重要的 我们目前对转移过程的理解所面临的挑战是缺乏可供研究的模型 转移的生理背景，特别是概括人类骨向性的模型 前列腺癌。 这项提议的首要目标是了解致命性疾病中的分子变化是如何存在的 前列腺癌对疾病结果的影响以及如何利用这一知识开发出更有效的 治疗。特别是，我的初步数据强烈表明MYC是骨转移进展的驱动因素。 鉴于传统上很难针对MYC进行治疗，这项提议将利用独特的鼠标 针对MYC信号依赖的特定治疗脆弱性的骨转移模型 前列腺癌患者。具体地说，在目标1中，我将研究ATAD2-溴域的小分子抑制作用 抑制转移和治疗耐药的策略。在目标2中，我将使用CRISPR屏幕来识别合成的 高MYC活性的前列腺癌的致命性脆弱性。在目标3中，我将利用CRISPR技术来 体细胞编辑小鼠前列腺的基因组，以简化表型研究 基因改变对前列腺癌进展的影响。 该奖项中概述的职业发展计划利用了我在哥伦比亚大学的培训和 杰出的顾问委员会进入创新的研究计划，将我的职业生涯引向特定的精确度 治疗前列腺癌骨转移的药物途径。这项提议将提供 竞争性R01提交的概念基础、初步数据和实验工具，因此 开始了我的独立事业。 如果成功，该奖项将为一类新的目标特工提供原则证明，并揭露 体内发生的转移性前列腺癌的新的治疗脆弱性。这项提议将推进 通过潜在地导致新的临床可测试的假说来指导临床试验。最终，这些 结果将通过降低与转移性前列腺癌相关的发病率和死亡率来影响患者的护理 癌症。

Project Summary/Abstract Prostate cancer lethality is mainly due to metastasis, which occurs most frequently in bone and is associated with high morbidity. Despite recent progress, current treatments are not curative and therefore new therapeutic strategies are urgently needed. Given that both metastatic progression and therapeutic resistance occur in the context of a whole organism and are influenced by the tumor microenvironment, one significant challenge to our current understanding of metastatic progression is the paucity of models in which to study metastasis in its physiological context, and especially models that recapitulate the bone tropism of human prostate cancer. The overarching goal of this proposal is to understand how the molecular alterations present in lethal prostate cancers contribute to disease outcome and how to use this knowledge to develop more effective therapies. In particular, my preliminary data strongly suggests MYC as a driver of bone metastasis progression. Given that MYC has traditionally been hard to target therapeutically, this proposal will leverage unique mouse models of bone metastasis to address specific therapeutic vulnerabilities to target MYC signaling dependencies in prostate cancer. Specifically, in Aim 1 I will study small molecule inhibition of the ATAD2-bromodomain as a strategy to inhibit metastasis and therapy resistance. In Aim 2, I will use CRISPR screens to identify synthetic lethal vulnerabilities of prostate tumors with high MYC activation. In Aim 3, I will exploit CRISPR technology to somatically edit the genomes of mouse prostates in order to streamline the study of the phenotypic consequences of genetic alterations for prostate cancer progression. The career development plan outlined in this award leverages my training at Columbia University and an outstanding advisory committee into an innovative research plan to steer my career into specific precision medicine approaches for the treatment of prostate cancer bone metastasis. This proposal will provide the conceptual groundwork, preliminary data and experimental tools for a competitive R01 submission, thus launching my independent career. If successful, this award will provide proof-of-principle for a new class of targeted agents and uncover new therapeutic vulnerabilities in metastatic prostate cancer as occurs in vivo. This proposal will advance the field by potentially leading to novel clinically testable hypotheses that may guide clinical trials. Ultimately, these results will impact patient care by reducing the morbidity and mortality associated with metastatic prostate cancer.