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.

项目摘要每年，美国约有8,000人被诊断出患有生殖细胞肿瘤（GCT）多数是发展睾丸GCT的年轻人。大多数患者用常规治愈化学疗法虽然复发了30％，并且其中一半的患者最终屈服于他们的疾病。鉴于这些患者的长寿预期寿命，当GCT死亡发生时，它是最大的丧生的任何非致金子恶性肿瘤的终身次数代表。我们以前的研究有证明GCTS表现出极大的杂合性丧失（RLOH）和高的负担线粒体启动的凋亡程度。该建议的目的是剖析分子特征该启动在GCT中启动RLOH，确定RLOH与缺陷DNA检查点之间的关系为肿瘤进步，并评估功能测定能力在化学疗法之前鉴定最高风险疾病的能力引发。长期目标是实现患者分层的新机制并确定新的机制化学耐药性GCT的治疗靶标，目前是未满足的医疗需求的领域正在调查的治疗选择。该提议的独特之处在于它利用了广泛的新颖性 Dana-Farber癌症研究所/哈佛大学癌症中心和麻省理工学院广泛研究所的资源哈佛大学以及一个国际合作者团队，以克服有限的临床前模型疾病并纳入以患者为中心的测定，重点是人类肿瘤样品，以解决这些假设此处概述了。提出的特定目的是：1）定义与倒数相关的遗传缺陷原代生殖细胞肿瘤中杂合性的丧失，2）确定肿瘤进化的分子特征导致化学耐药细胞肿瘤，3）评估多能标记的临床实用性 GCT结果的预后。这些研究将定义GCT中RLOH的减数分裂缺陷，确定启动致命化学抗性的次级分子缺陷，并揭示了增强患者的靶标分层和治疗发展。此外，这些努力将加速新的发展探索基因组和表观基因组的综合分子分析的计算算法解决有关致癌发展和发展到化学抗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，并更广泛地作为创新模型研究罕见的癌症。