Mechanisms and Treatment of PTEN Mutant Prostate Tumorigenesis

PTEN突变前列腺肿瘤发生机制及治疗

• 批准号: 8433517
• 负责人: Lloyd C Trotman
• 金额: $ 28.61万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433517
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Biological Markers; Biological Models; Biopsy; Candidate Disease Gene; Cell Aging; Cell Proliferation; Cell Survival; Cells; Clinical Data; Diagnosis; Disease; Event; Exhibits; Gene Mutation; Genes; Genetic; Genetic Models; Genomics; Goals; Human; Immunohistochemistry; In Vitro; Knowledge; Lead; Link; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of prostate; Mediating; Memorial Sloan-Kettering Cancer Center; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Bank; Monitor; Mus; Mutant Strains Mice; Mutate; Mutation; Neoplasms; Nuclear; PIK3CG gene; PTEN gene; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Process; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Proteins; Proto-Oncogene Proteins c-akt; RNA Interference; Recurrence; Research; Resistance; Route; Sampling; Shapes; Signal Pathway; Signal Transduction; Technology; Testing; Therapeutic; Tissue Microarray; Tissues; Translating; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; Validation; Work; abstracting; addiction; base; cancer genome; cancer genomics; cell growth; clinically relevant; genetic analysis; genome-wide; genome-wide analysis; in vivo; inhibitor/antagonist; insight; kinase inhibitor; malignant breast neoplasm; men; mouse model; mutant; novel; novel therapeutic intervention; prevent; prostate carcinogenesis; research study; response; restoration; senescence; tumor; tumor initiation; tumor progression; tumorigenesis

Project Summary / Abstract Mechanisms and Treatment of PTEN Mutant Prostate Tumorigenesis PTEN is a tumor suppressor that is among the most frequently lost or mutated genes of human cancer. More than half of the 220,000 men diagnosed with prostate cancer in the United States each year will likely exhibit alterations of PTEN at the gene or protein level. PTEN is unique in its reversal of PI 3-Kinase activity, which promotes cell survival and proliferation, a signaling pathway which is deregulated in a majority of human prostate, breast and brain cancers. My research is combining mouse modeling with genetic analysis of human cancer to understand the molecular mechanism of prostate cancer. Previously, I demonstrated that haploinsufficiency of PTEN can lead directly to prostate cancer without an obligatory "second-hit" in the PTEN gene. Moreover haploinsufficiency of additional tumor suppressor genes such as PML can cooperate with partial PTEN-loss to form cancer. We have further shown that in normal prostate cells, complete loss of PTEN prevents tumorigenesis by triggering cellular senescence, an irreversible cell growth arrest. Together, these findings provide the first evidence of why haploinsufficiency of a major tumor suppressor can be favored over complete loss in tumors. Since the senescence response is entirely dependent on intact p53 function, these insights led to a conceptual breakthrough in the mechanism of interaction between these two major tumor suppressors. Now, we are using a cross-species oncogenomics approach as our collaborators at Memorial Sloan Kettering Cancer Center are generating comprehensive libraries of molecular alterations in over 200 patient samples. Through this effort, we are now uncovering the causal link between loss of PTEN and novel genes in metastatic prostate cancer. Our aims are: (1) to use comprehensive analysis of primary and metastatic human prostate cancer to identify tumor suppressors in the PI 3-Kinase pathway that cooperate with PTEN-alteration and to then explore their mechanisms of action in vitro and in vivo. Our preliminary work has already successfully identified a novel PTEN-cooperating tumor suppressor of metastatic prostate cancer. (2) to determine when, in which genetic context, and how Pten-restoration can revert established tumors using our newly developed in vivo inducible RNA-interference technology. Our primary objective is to determine if tumors with Pten-loss alone or when combined with the newly identified tumor suppressor from Aim 1 still respond to Pten restoration (addiction), or if they become pathway independent due to additional spontaneous genomic alterations. We monitor recurrent alterations through genome-wide copy number analysis to identify the potential escape routes. This research thus will lay the groundwork for therapeutic decisions in advanced prostate cancer by identifying a potential signature that is associated with PI 3-Kinase inhibitor sensitivity or resistance.

项目总结/摘要 PTEN突变型前列腺肿瘤的发生机制及治疗 PTEN是一种肿瘤抑制基因，是人类最常丢失或突变的基因之一， 癌在美国，220，000名被诊断患有前列腺癌的男性中， 一年后可能会在基因或蛋白质水平上表现出PTEN的改变。PTEN在逆转 PI 3-激酶活性，其促进细胞存活和增殖，这是一种信号通路， 在大多数人类前列腺癌、乳腺癌和脑癌中，我的研究是把老鼠 通过对人类癌症的遗传分析建立模型，以了解前列腺癌的分子机制 癌以前，我证明了PTEN的单倍不足可以直接导致前列腺癌 而不需要在PTEN基因中进行强制性的“二次打击”。此外，额外肿瘤的单倍不足 抑制基因如PML可与部分PTEN缺失协同形成癌症。 我们进一步表明，在正常前列腺细胞中，PTEN的完全缺失可以防止肿瘤发生。 通过触发细胞衰老，不可逆转的细胞生长停滞。总之，这些发现提供了 第一个证据表明为什么主要肿瘤抑制因子的单倍不足可能优于完全丧失 在肿瘤中。由于衰老反应完全依赖于完整的p53功能，这些见解导致 这两种主要肿瘤之间相互作用机制的概念性突破 抑制剂现在，我们正在使用跨物种的癌基因组学方法，作为我们的合作者， 纪念斯隆凯特琳癌症中心正在生成分子改变的综合库 在超过200个病人样本中通过这一努力，我们现在正在揭示的因果关系之间的损失， 转移性前列腺癌中的PTEN和新基因。 我们的目标是： (1)使用原发性和转移性人前列腺癌的综合分析来识别肿瘤 PI 3-激酶途径中与PTEN改变合作的抑制因子，然后探索它们的作用 体外和体内的作用机制。我们的初步工作已经成功地确定了一个 转移性前列腺癌的新型PTEN协同肿瘤抑制剂。 (2)以确定何时，在何种遗传背景下，以及如何Pten恢复可以恢复建立 使用我们新开发的体内可诱导RNA干扰技术。我们的首要目标 是为了确定是否有单独的Pten丢失的肿瘤，或者当与新发现的肿瘤结合时， 来自Aim 1抑制子仍然对Pten恢复（成瘾）有反应，或者如果它们成为通路 由于额外的自发性基因组改变而独立。我们监测经常性的改动 通过全基因组拷贝数分析来确定潜在的逃逸途径。因此，这项研究 将为晚期前列腺癌的治疗决策奠定基础， 与PI 3-激酶抑制剂敏感性或抗性相关的信号。