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。大多数患者通过常规化疗治愈， 尽管30%的患者会复发，并且这些患者中有一半最终死于疾病。考虑到人类的寿命 在这些患者中，当发生GCT死亡时，它占了生命年损失的最大数量。 任何非儿童恶性肿瘤代表。我们以前的研究表明，GCT表现出 极端的杂合性相互丢失（RLOH）负担和高度的线粒体启动， 凋亡该建议的目的是剖析GCT中引发RLOH的分子特征， RLOH和缺陷DNA检查点之间的关系作为肿瘤的进展，并评估的能力， 在化疗开始前进行功能测定以识别最高风险疾病。长期目标是 使患者分层的新机制成为可能，并确定耐药GCT的新治疗靶点， 目前，这是一个医疗需求未得到满足的领域，正在研究的治疗选择极其有限。这 该提案的独特之处在于，它利用了丹娜-法伯癌症研究所（Dana-Farber Cancer） 研究所/哈佛癌症中心和麻省理工学院和哈佛的布罗德研究所，沿着一个国际团队， 合作者，以克服这种疾病的有限临床前模型，并纳入以患者为中心的测定 集中于人类肿瘤样品以解决本文概述的假设。拟议的具体目标是： 1)确定原发性生殖细胞肿瘤中与杂合性相互丢失相关的遗传缺陷，2） 确定导致化疗耐药生殖细胞肿瘤的肿瘤演变的分子特征，以及3） 评估多能性标志物作为GCT预后的临床效用。这些研究将确定 GCTs中RLOH潜在的减数分裂缺陷，确定启动致死性的次级分子缺陷 化疗耐药性，并揭示了增强患者分层和治疗发展的目标。此外，本发明还提供了一种方法， 这些努力将加速新的计算算法的开发， 分析基因组和表观基因组，以解决有关致癌发展的特定假设 以及发展为具有广泛适用性的化学抗性。最后，该项目将加速 GCT的临床和分子特征，探索驱动这种罕见肿瘤类型的潜在生物学， 更广泛地作为研究罕见癌症的创新模型。

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.