Mechanisms and Treatment of PTEN Mutant Prostate Tumorigenesis

描述（由申请人提供）：PTEN是一种肿瘤抑制因子，是人类癌症中最常丢失或突变的基因之一。在美国，每年确诊为前列腺癌的22万男性中，超过一半的人可能在基因或蛋白质水平上表现出PTEN的改变。PTEN在其逆转PI 3-激酶活性方面是独一无二的，PI 3-激酶活性促进细胞存活和增殖，这是一种在大多数人类前列腺癌、乳腺癌和脑癌中不受调节的信号通路。我的研究是将小鼠建模与人类癌症基因分析相结合，了解前列腺癌的分子机制。先前，我证明了PTEN的单倍不足可以直接导致前列腺癌，而不需要PTEN基因的强制性“二次打击”。此外，其他肿瘤抑制基因（如PML）的单倍性不足可与pten的部分缺失协同形成癌症。我们进一步表明，在正常的前列腺细胞中，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）来防止肿瘤的发生。总之，这些发现提供了第一个证据，说明为什么肿瘤中主要肿瘤抑制因子的单倍体不足比完全丧失更有利。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种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肿瘤基因组学方法，因为我们在纪念斯隆凯特琳癌症中心的合作者正在建立200多个患者样本的分子改变综合库。通过这一努力，我们现在发现了转移性前列腺癌中PTEN缺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人前列腺癌的综合分析，发现PI 3-激酶通路中与pten改变相关的抑癌因子，并探讨其体内外作用机制。我们的初步工作已经成功地发现了一种新的pten合作的转移性前列腺癌肿瘤抑制因子。(2)利用我们新开发的体内诱导rna干扰技术，确定pten修复何时、在何种遗传背景下以及如何恢复已建立的肿瘤。我们的主要目的是确定单独Pten缺失的肿瘤或与Aim 1中新发现的肿瘤抑制因子联合时是否仍然对Pten恢复（成瘾）有反应，或者它们是否由于额外的自发基因组改变而成为途径独立。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，该研究将通过确定与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。

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.