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: 8033168
• 负责人: Lloyd C Trotman
• 金额: $ 24.05万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033168
• 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; 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; public health relevance; research study; response; restoration; senescence; tumor; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The PTEN tumor suppressor is frequently affected in human cancer and our recent findings have unraveled an unexpected mechanism for tumor initiation and progression in this event. We are now investigating novel components of this prostate cancer pathway and explore how our insights can be translated into therapy. The function of the PTEN tumor suppressor is compromised in a majority of human cancer malignancies. We are just beginning to understand how cells and tissues react to this insult since it is becoming clear that PTEN is haploinsufficient and that complete loss triggers cellular senescence. These findings have led us to explore the human cancer genome and to a process for identification of novel genes that cause metastatic prostate cancer. By identifying how haploinsufficiency and senescence shape PTEN-mutant lethal prostate cancer we will better understand the principles that underlie much of this disease and create new therapeutic approaches.

描述（由申请人提供）：PTEN是一种肿瘤抑制基因，是人类癌症中最常丢失或突变的基因之一。在美国，每年被诊断患有前列腺癌的220，000名男性中有一半以上可能会在基因或蛋白质水平上表现出PTEN的改变。PTEN在其PI 3-激酶活性的逆转方面是独特的，PI 3-激酶活性促进细胞存活和增殖，这是一种在大多数人前列腺癌、乳腺癌和脑癌中失调的信号传导途径。我的研究是将小鼠模型与人类癌症的遗传分析相结合，以了解前列腺癌的分子机制。以前，我证明了PTEN的单倍不足可以直接导致前列腺癌，而不会在PTEN基因中产生强制性的“二次打击”。此外，额外的肿瘤抑制基因如PML的单倍不足可以与部分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的完全缺失通过触发细胞衰老（一种不可逆的细胞生长停滞）来防止肿瘤发生。总之，这些发现提供了第一个证据，证明为什么主要肿瘤抑制因子的单倍不足可以优于肿瘤的完全丧失。由于衰老反应完全依赖于完整的p53功能，这些见解导致了这两个主要肿瘤抑制因子之间相互作用机制的概念突破。现在，我们正在使用跨物种的癌基因组学方法，因为我们在纪念斯隆-凯特琳癌症中心的合作者正在200多个患者样本中生成全面的分子改变库。通过这一努力，我们现在正在揭示转移性前列腺癌中PTEN丢失和新基因之间的因果关系。 我们的目标是：（1）通过对原发性和转移性前列腺癌的综合分析，鉴定PI 3-激酶通路中与PTEN改变协同作用的肿瘤抑制因子，并在体外和体内探索其作用机制。我们的初步工作已经成功地确定了一种新的PTEN协同转移性前列腺癌的肿瘤抑制因子。 (2)确定何时，在何种遗传背景下，以及如何使用我们新开发的体内诱导RNA干扰技术，Pten恢复可以恢复已建立的肿瘤。我们的主要目的是确定肿瘤与Pten损失单独或当与新发现的肿瘤抑制剂Aim 1仍然响应Pten恢复（成瘾），或者如果他们成为途径独立由于额外的自发基因组改变。我们通过全基因组拷贝数分析来监测复发性改变，以确定潜在的逃逸途径。因此，这项研究将通过识别与PI 3-激酶抑制剂敏感性或耐药性相关的潜在特征，为晚期前列腺癌的治疗决策奠定基础。 公共卫生关系：PTEN肿瘤抑制因子在人类癌症中经常受到影响，我们最近的研究结果揭示了这种事件中肿瘤发生和进展的意外机制。我们现在正在研究这种前列腺癌途径的新成分，并探索如何将我们的见解转化为治疗。PTEN肿瘤抑制因子的功能在大多数人类恶性肿瘤中受到损害。我们刚刚开始了解细胞和组织如何对这种损伤作出反应，因为很明显，PTEN是单倍不足的，完全丧失会引发细胞衰老。这些发现促使我们探索人类癌症基因组，并找到了识别导致转移性前列腺癌的新基因的方法。通过确定单倍不足和衰老如何塑造PTEN突变型致命前列腺癌，我们将更好地理解这种疾病的基本原理，并创造新的治疗方法。