Molecular origins and evolution to chemoresistance in germ cell tumors

项目摘要 美国每年约有8,000人被诊断患有生殖细胞肿瘤（GCT）， 大多数是发展睾丸GCT的年轻男性。大多数病人都是用传统的 化疗，虽然30%复发，一半的患者最终死于他们的疾病。鉴于 这些患者的预期寿命长，当发生GCT死亡时，它占最大的 任何非儿童期恶性肿瘤的生命年损失。我们以往的研究 表明GCT表现出极端的杂合性互失（RLOH）负担， 线粒体对凋亡的启动程度。这项提案的目的是剖析 在GCT中启动RLOH，确定RLOH与肿瘤缺陷DNA检查点之间的关系， 进展，并评估功能测定在化疗前识别最高风险疾病的能力 入会仪式长期目标是启用患者分层的新机制，并确定新的 化疗耐药GCT的治疗靶点，目前是一个未满足的医疗需求领域， 正在研究的治疗方案。这项提案的独特之处在于，它利用了广泛而新颖的 丹娜-法伯癌症研究所/哈佛癌症中心和麻省理工学院布罗德研究所的资源， 哈佛，沿着一个国际合作者小组，克服有限的临床前模型， 并结合以患者为中心的检测，重点关注人类肿瘤样本，以解决假设 在此概述。提出的具体目标是：1）定义与互惠相关的遗传缺陷 原发性生殖细胞肿瘤的杂合性丢失，2）确定肿瘤演变的分子特征 导致化学抗性生殖细胞肿瘤，和3）评估多能性标志物作为 GCT预后。这些研究将确定GCT中RLOH背后的减数分裂缺陷， 引发致命的化学抗性的次级分子缺陷，并揭示了增强患者的靶点， 分层和治疗发展。此外，这些努力将加快新的 计算算法探索基因组和表观基因组的综合分子分析， 阐述了关于致癌发展和进展到化疗耐药性的特定假设， 具有广泛的适用性。最后，该项目将加速GCT的临床和分子表征， 探索驱动这种罕见肿瘤类型的潜在生物学，并更广泛地作为一种创新模型， 研究罕见的癌症

PROJECT SUMMARY Approximately 8,000 people in the U.S. are diagnosed with germ cell tumors (GCTs) each year, and the vast majority are young men who develop testicular GCTs. Most patients are cured with conventional chemotherapy, although 30% recur, and half of such patients ultimately succumb to their disease. Given the long life expectancy of these patients, when death from GCT occurs, it accounts for among the greatest number of life years lost of any non-childhood malignancy representing. Our previous studies have demonstrated that GCTs exhibit an extreme burden of reciprocal loss of heterozygosity (RLOH) and high degree of mitochondrial priming for apoptosis. The goal of this proposal is to dissect the molecular features that initiate RLOH in GCTs, determine the relationship between RLOH and defect DNA checkpoints as tumors progress, and evaluate the ability of functional assays to identify highest risk disease prior to chemotherapy initiation. The long-term objective is to enable new mechanisms of patient stratification and identify new therapeutic targets for chemoresistant GCTs, currently an area of unmet medical need with extremely limited therapeutic options under investigation. This proposal is unique in that it leverages the extensive and novel resources at both the Dana-Farber Cancer Institute/Harvard Cancer Center and the Broad Institute of MIT and Harvard, along with an international team of collaborators, to overcome limited preclinical models of this disease and incorporate patient-centered assays focused on human tumor samples to address the hypotheses outlined herein. The proposed specific aims are: 1) To define the genetic defects associated with reciprocal loss of heterozygosity in primary germ cell tumors, 2) To identify the molecular features of tumor evolution leading to chemoresistant germ cell tumors, and 3) To assess the clinical utility of pluripotency markers as prognostic for GCT outcomes. These studies will define the meiotic defects underlying RLOH in GCTs, identify the secondary molecular defects that initiate lethal chemoresistance, and reveal targets for enhanced patient stratification and therapeutic development. In addition, these efforts will accelerate development of new computational algorithms that explore integrative molecular analyses of both the genome and epigenome to address specific hypotheses regarding oncogenic development and progression to chemoresistance that may have broad applicability. Finally, this project will accelerate the clinical and molecular characterization of GCTs, explore the underlying biology driving this rare tumor type, and serve more broadly as an innovative model for studying rare cancers.