Molecular origins and evolution to chemoresistance in germ cell tumors

生殖细胞肿瘤中化学耐药性的分子起源和进化

基本信息

批准号：
10443070
负责人：
Eliezer M Van Allen
金额：
$ 40.99万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443070
关键词：
Acceleration Activities of Daily Living Address Affect Algorithms Alleles Apoptosis Apoptotic Area Automobile Driving Award Biological Assay Biology Cancer Biology Cancer Center Cessation of life Chemoresistance Chromosomes Clinical Clinical assessments Computational Biology Computational algorithm DNA DNA copy number Dana-Farber Cancer Institute Data Defect Development Diagnosis Disease Disease model Dissection Early identification Epigenetic Process Event Evolution Exhibits Foundations Genes Genetic Genetic Processes Genetic Transcription Genome Genomics Germ cell tumor Goals Human Individual Infrastructure Institution Interdisciplinary Study International Investigation Life Expectancy Loss of Heterozygosity Malignant Neoplasms Mediastinum Medical Meiosis Meiotic Recombination Mitochondria Modeling Molecular Molecular Analysis Mutation Oncogenic Oncology Outcome Ovary Patients Pattern Persons Phenotype Platinum Pre-Clinical Model Predisposition Procedures Recurrence Refractory Disease Research Resistance Resources Sampling Sentinel Somatic Mutation Specimen Stratification Study models Techniques Testicular Germ Cell Tumor Testis Therapeutic Translating Translations Urogenital Cancer Work arm cancer genetics cancer type chemotherapy clinically actionable disorder risk epigenetic silencing epigenome experimental study genome analysis high risk innovation mortality new therapeutic target novel patient oriented patient stratification pluripotency prognostic programs rare cancer relapse prediction therapeutic development therapy resistant transcriptomics treatment strategy tumor tumor initiation tumor progression tumorigenesis years of life lost young man

项目摘要

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.

项目概要美国每年约有 8,000 人被诊断患有生殖细胞肿瘤 (GCT)，大多数是发生睾丸 GCT 的年轻男性。大多数患者通过常规治疗可以治愈化疗，尽管 30% 会复发，而且其中一半的患者最终死于疾病。鉴于这些患者的预期寿命很长，当发生 GCT 死亡时，它占最大的比例之一代表任何非儿童期恶性肿瘤损失的生命年数。我们之前的研究有证明 GCT 表现出杂合性相互损失 (RLOH) 的极端负担和高线粒体启动细胞凋亡的程度。该提案的目标是剖析分子特征在 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引发。长期目标是启用患者分层的新机制并确定新的耐药 GCT 的治疗靶点，目前是一个医疗需求未得到满足的领域，且极其有限治疗方案正在研究中。该提案的独特之处在于它利用了广泛且新颖的丹纳法伯癌症研究所/哈佛大学癌症中心和麻省理工学院博德研究所的资源哈佛大学与国际合作者团队一起克服了这一问题的有限临床前模型疾病并结合以患者为中心的针对人类肿瘤样本的检测来解决假设在此概述。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杂合性缺失，2) 鉴定肿瘤进化的分子特征导致化疗耐药的生殖细胞肿瘤，以及 3) 评估多能性标记物的临床效用 GCT 结果的预后。这些研究将定义 GCT 中 RLOH 的减数分裂缺陷，确定引发致命化疗耐药性的继发性分子缺陷，并揭示增强患者的靶标分层和治疗发展。此外，这些努力将加速新产品的开发探索基因组和表观基因组综合分子分析的计算算法解决有关致癌发展和化学耐药性进展的具体假设，这些假设可能具有广泛的适用性。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，并更广泛地作为创新模型研究罕见癌症。