A Prostate Cancer Dependency Map to Identify Tumor Subtype-Specific Vulnerabilities

项目总结/摘要 尽管我们在癌症生物学方面的知识取得了进步，食品和药物管理局批准了新的癌症药物， 和药物管理局（FDA），很少有实体瘤患者已经扩散到远处 （转移）治愈了他们的疾病。转移性前列腺癌（mPC）也是如此。因此，委员会认为， 大量的研究是为了确定新的靶点和治疗方法。 我们和其他人开发的新技术，现在提供了前所未有的方法， 全面深入地描述肿瘤的特征。使用这些方法的研究已经确定 mPC由多个不同的亚型组成-其中一个亚型由特定的基因组定义， 癌基因和正常抑制肿瘤生长的基因的改变。其他人则由 表型-影响功能和行为的特征。值得注意的是，这些亚型中的一些现在 已知对特定疗法有不同的脆弱性-知识， 治疗方法。然而，对于大多数亚型，我们目前还不知道它们的具体情况。 我们也没有治疗方法可以阻止它们的生长/进展。 强大的高通量方法来剖析特定癌症基因组中每个基因的功能 已被用于构建许多癌症类型中的癌症依赖性图（DEPMAP）。这些 这些方法是高度“发现驱动”的，因为它们解决了识别癌症脆弱性的问题， 系统化而不是假设驱动的方式。然而，前列腺癌在很大程度上被排除在这些之外。 由于可用于进行这些大规模活动的mPC型号数量非常有限，因此国际项目 实验 在这项提案中，我们的目标是确定晚期致命性前列腺癌的新治疗途径。我们将使用 我们已经开发并表征了多种新的转移性前列腺癌模型， 使用全基因组功能丧失筛选子类型特异性依赖性。同时，我们将评估 批准的药剂以及开发中的化合物的药物库的生长抑制作用。 将针对一组患者在体内测试利用基因组依赖性的药剂的组合。 具有和不具有预测的脆弱性的衍生的异种移植物（PDX）系。

PROJECT SUMMARY/ABSTRACT Despite the advances in our knowledge of cancer biology and the approval of new cancer drugs by the Food and Drug Administration (FDA), very few patients with solid tumors that have spread to distant sites (metastases) are cured of their disease. This is true of metastatic prostate cancer (mPC). Consequently, substantial research is directed toward identifying new targets and treatments. New technologies which we and others have developed, now provide unprecedented approaches for deeply characterizing tumors on a comprehensive scale. Studies using these approaches have determined that mPC is comprised of multiple distinct subtypes – a subset of these are defined by specific genomic alterations in oncogenes and genes that normally function to suppress tumor growth. Others are defined by the phenotype – characteristics that influence function and behavior. Notably, a number of these subtypes are now known to have different vulnerabilities to particular therapies – knowledge that underlies a more precision approach for treatment. However, for most subtypes we do not currently have knowledge of their particular vulnerabilities nor do we have therapeutics that can halt their growth/progression. Powerful high-throughput approaches to dissect the function of every gene in a particular cancer genome have been deployed to construct cancer dependency maps (DEPMAP) in many cancer types. These approaches are highly ‘discovery driven’ as they approach the problem of identifying cancer vulnerabilities in a systematic rather than hypothesis-driven fashion. However, prostate cancer is largely excluded from these International projects due to the very limited number of mPC models available to conduct these large scale experiments. In this proposal, we aim to identify new treatment avenues for advanced lethal prostate cancer. We will use multiple new models of metastatic prostate cancer that we have developed and characterized to identify PC subtype specific dependencies using genome-wide loss-of-function screens. In parallel, we will evaluate growth inhibitory effects of drug libraries of approved agents as well as compounds in development. Combinations of agents that exploit genomic dependencies will be tested in vivo against a panel of patient derived xenograft (PDX) lines with and without the predicted vulnerability.