Molecular Signatures of Lethal and Indolent Prostate Cancer

描述（由申请人提供）：具体目标。前列腺癌（PCA）是一种分子异质性疾病，具有从惰性到高度侵袭性的多种临床谱。PCA的一个晚期表现是进展到神经内分泌表型，这是普遍致命的，平均生存时间不到一年。据估计，30%的晚期前列腺癌转化为神经内分泌前列腺癌（NEPC），并可能选择或加速使用雄激素剥夺疗法。随着更有效的激素治疗进入临床领域（如阿比特龙、MDV3100）， NEPC的发病率预计会上升。我们从全基因组DNA和RNA测序中获得了初步数据，使我们假设NEPC起源于腺癌（AdCa），并且分子事件决定了从激素naïve AdCa到致死性NEPC的进展。因此，我们提出3个具体目标来阐明NEPC的关键分子驱动因素。具体目标1：定义与NEPC出现相关的体细胞拷贝数改变。本研究的工作假设是，在神经内分泌去分化发展之前，存在与NEPC相关的复发性体细胞拷贝数改变（SCNA）。在本Aim的结论中，我们将提名多达20个来自SCNA位点的基因，这些基因在NEPC中复发，而在AdCa中不常见，转录支持表明这些基因是功能获得（癌基因）或功能丧失（肿瘤抑制基因）基因。具体目标2：确定NEPC中观察到的突变谱。该Aim的工作假设是，NEPC具有特定的驱动突变特征。在本研究结束时，我们预计这些突变和重排的一个子集有助于神经内分泌去分化。我们预计提名多达20个突变将适合进一步的分子功能评估。特异性目的3确定NEPC基因的功能活性。本目标的工作假设是，目标1-2中指定的基因子集的改变是功能突变的获得或丧失。在本Aim的结论中，我们将提名多达5个功能活跃的基因，这些基因存在于NEPC和AdCa的一个子集中。作为另一项资助的一部分，我们将立即使用异种移植模型对这些基因进行后续研究（本申请不建议进行动物实验）。我们相信，提出的研究将使我们对PCA的高度侵袭性形式有新的认识。

DESCRIPTION (provided by applicant): Specific Aim. Prostate cancer (PCA) is a molecularly heterogeneous disease with a varied clinical spectrum ranging from indolent to highly aggressive. One late manifestation of PCA is progression to a neuroendocrine phenotype, which is universally lethal with an average survival of less than one year. It is estimated that 30% of late stage PCA transforms to neuroendocrine prostate cancer (NEPC), and potentially selected for or accelerated by the use of androgen deprivation therapies. With the introduction of more potent hormonal therapy into the clinical arena (e.g., Abiraterone, MDV3100), the incidence of NEPC is expected to escalate. We have generated preliminary data from Whole Genome DNA and RNA Sequencing leading us to hypothesize that NEPC arises from adenocarcinoma (AdCa) and that telltale molecular events determine a progression from hormone naïve AdCa to lethal NEPC. Therefore, we propose 3 Specific Aims to elucidate the key molecular drivers of NEPC. Specific Aim 1: Define Somatic Copy Number Alterations Associated with the Emergence of NEPC. The working hypothesis of this Aim is that there are recurrent somatic copy number alterations (SCNA) associated with NEPC detectable prior to the development of neuroendocrine de-differentiation. At the conclusion of this Aim, we will nominate up to 20 genes from SCNA loci that are recurrent in NEPC and less common in AdCa with transcriptional support suggesting that these are gain of function (oncogenes) or loss of function (tumor suppressor) genes. Specific Aim 2: Determine Spectrum of Mutations Observed in NEPC. The working hypothesis of this Aim is that there are specific driving mutations that characterize NEPC. At the end of this Aim, we anticipate that a subset of these mutations and rearrangements contribute to neuroendocrine de-differentiation. We anticipate nominating up to 20 mutations that will be appropriate for further molecular functional evaluation. Specific Aim 3 Determine the Functional Activity of NEPC Genes. The working hypothesis of this Aim is that alterations in a subset of the genes nominated in Aims 1-2 are gain or loss of function mutations. At the conclusion of this Aim we will have nominated up to 5 functionally active genes that are present in NEPC and a subset of AdCa. We will immediately follow up on these genes using xenograft models as part of another funded grant (no animal experiments are proposed in this application). We believe that the proposed studies will allow us new insight into a highly aggressive form of PCA.