Molecular Origins and Evolution to Chemoresistance in Germ Cell Tumors

项目总结 在美国，每年约有8000人被诊断出患有生殖细胞肿瘤(GCT)，而大量的 大多数是患有睾丸GCTS的年轻男性。大多数患者都是通过常规化疗治愈的， 尽管30%的患者复发，其中一半的患者最终死于他们的疾病。考虑到较长的预期寿命 在这些患者中，当死于GCT时，它是造成最多生命年损失的原因之一 任何非儿童期的恶性肿瘤都代表。我们之前的研究表明，GCTS表现出一种 互惠杂合性缺失(RLOH)和高度线粒体启动的极端负担 细胞凋亡。这项建议的目标是剖析在GCTS中启动RLOH的分子特征，确定 RLOH与DNA缺陷检查点在肿瘤进展过程中的关系 在化疗开始前进行功能分析，以确定高危疾病。长期目标是 启用患者分层的新机制，并确定化疗耐药GCTS的新治疗靶点， 目前，这是一个未得到满足的医疗需求领域，正在调查的治疗选择极其有限。这 Proposal是独一无二的，因为它利用了Dana-Farber癌症中心广泛而新颖的资源 研究所/哈佛癌症中心和麻省理工学院和哈佛大学的博德研究所，以及一个国际团队 合作者，克服这种疾病有限的临床前模型，并纳入以患者为中心的分析 聚焦于人类肿瘤样本，以解决这里概述的假设。建议的具体目标是： 1)确定与原发生殖细胞肿瘤的杂合性互换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进化的分子特征，以及3) 评估多能性标记物作为预测GCT结果的临床实用性。这些研究将定义 GCTS中RLOH潜在的减数分裂缺陷，识别引发致死的次级分子缺陷 化疗耐药性，并揭示了加强患者分层和治疗开发的目标。此外, 这些努力将加速探索整合分子的新计算算法的开发 分析基因组和表观基因组以解决有关致癌发展的特定假说 并进展为可能具有广泛适用性的化疗耐药。最后，这个项目将加速 GCTS的临床和分子特征，探索这种罕见肿瘤类型的潜在生物学驱动因素，以及 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.