Perioperative Targeted Genotyping in Glioma

胶质瘤围手术期靶向基因分型

基本信息

批准号：
10578703
负责人：
Ganesh Shankar
金额：
$ 19.33万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10578703
关键词：
Address Adjuvant Radiotherapy Adjuvant Therapy Adult Alleles Area BRAF gene Biological Assay Biopsy Biopsy Specimen Blood Blood specimen Brain Brain Neoplasms CLIA certified Cancer Detection Cells Central Nervous System Neoplasms Cephalic Cerebrospinal Fluid Characteristics Child Clinical Clinical Management Collaborations Core Biopsy DNA analysis Data Detection Diagnosis Diagnostic Procedure Diffuse Diffuse astrocytoma Disease Early Diagnosis Excision Failure Frozen Sections Gene Frequency General Hospitals Genes Genomics Genotype Glioblastoma Glioma Guanine + Cytosine Composition Histologic Histology Immunohistochemistry K-Series Research Career Programs Learning Lesion Malignant Neoplasms Massachusetts Measures Mentors Mentorship Metastatic Melanoma Methods Molecular Molecular Diagnosis Molecular Genetics Monitor Mutation Mutation Analysis Mutation Detection Natural History Neoplasm Metastasis Neurosurgeon Oligodendroglioma-Astrocytoma Oligonucleotides Oncologist Operative Surgical Procedures Pathologic Pathologist Pathology Patients Pattern Peptide Nucleic Acids Perioperative Pilocytic Astrocytoma Postoperative Period Probability Process Recurrence Research Resected Risk Secure Sensitivity and Specificity Solid Solid Neoplasm Somatic Mutation Specific qualifier value Specimen Spinal Surgical margins Techniques Testing Therapeutic Time Training Variant Vertebral column Work chromatin remodeling clinically relevant cohort density design detection assay exosome improved liquid biopsy locked nucleic acid longitudinal analysis meetings melanoma molecular diagnostics mutant oligodendroglioma predicting response promoter prospective research clinical testing response segregation spatiotemporal treatment response tumor tumor DNA tumor progression young adult

项目摘要

Project Abstract The candidate is an academic neurosurgeon at Massachusetts General Hospital with training in the management of cranial and spinal oncologic diseases. He has an established track record in contributing to the genomics of central nervous system tumors. Through carefully selected mentors and collaborators, coursework, and meetings, the candidate seeks to develop an independent research effort at the completion of this career development award. His primary mentor is Dr. Bob Carter, who has significant expertise in the characterization of circulating exosomes from patients with glioma. The proposal is to further develop the candidate's research effort on perioperative genotyping of tumors of both solid and liquid biopsies. Gliomas are a group of intrinsic primary central nervous system tumors, with widely-ranging natural history and different treatment. Recent studies have identified recurrent mutations in IDH, TERT promoter, H3F3A, and BRAF that resolve the expected survival and response to therapies. The candidate has previously developed a rapid and sensitive genotyping assay that can detect these mutations within 30 minutes to secure an intraoperative molecular diagnosis of a glioma specimen. The first aim will be to establish the genotyping assay as a clinical test for as an adjunct for intraoperative diagnosis and perioperative monitoring. First, under mentorship from Dr. Iafrate and Dr. Lennerz, pathologists who specialize in molecular diagnostics, the candidate will learn the process of CLIA-certification in order to establish the described genotyping assay as a clinical test. This test will then be used to analyze stereotactic brain biopsies together with Dr. Stemmer-Rachamimov, a neuropathologist, to determine if augmenting frozen section analysis with molecular information results in achieving a pathologic diagnosis from an earlier core biopsy. In the second aim, the candidate will work with Dr. Cahill, a neurosurgeon, to obtain marginal biopsies from glioma resection to quantify tumor mutation allele fraction using the qPCR-based approach. This cohort will then be followed prospectively to correlate the spatiotemporal risk profile of tumor progression with the calculated allele fraction; the results of which could have implications on adjuvant radiation therapy field planning. In the third aim, blood samples will be prospectively collected from patients with glioma at specified time points with support from Dr. Batchelor, a neuro-oncologist. The cell free tumor DNA fraction from these specimens will be analyzed for the recurrent hotspot mutations covered in this assay. The detection of low abundance alleles in liquid biopsies is challenging and Dr. Carter's research expertise will guide the candidate's technical approach. Incidentally, BRAF and TERT promoter mutations are highly prevalent in malignant melanoma. Therefore, in collaboration with Dr. Sullivan, a melanoma oncologist, the candidate will apply this approach to the longitudinal analysis of blood samples obtained from patients with metastatic melanoma to assess treatment response. Collectively, the hypothesis to be tested is that if perioperative targeted mutational analysis of solid tumor specimens and liquid biopsies further establishes pathologic diagnosis and assessment of treatment response, respectively, then a clinical assay that provides this information can guide surgical and adjuvant therapy decisions. We propose that a similar approach can be similarly extended to other solid tumors characterized by well-defined mutations.

项目摘要该候选人是马萨诸塞州总医院的一名学术神经外科医生，接受过管理培训颅骨和脊柱肿瘤疾病。他在为中枢基因组学做出贡献方面有着良好的记录。神经系统肿瘤。通过精心挑选的导师和合作者、课程作业和会议，候选人寻求在完成该职业发展奖后开展独立研究工作。他的主要导师 Bob Carter 博士在神经胶质瘤患者循环外泌体的表征方面拥有丰富的专业知识。该提案旨在进一步发展候选人在实体瘤和实体瘤围手术期基因分型方面的研究工作。液体活检。神经胶质瘤是一组固有的原发性中枢神经系统肿瘤，具有广泛的自然史以及不同的待遇。最近的研究发现 IDH、TERT 启动子、H3F3A 和 BRAF 中存在反复突变解决预期的生存率和对治疗的反应。候选人之前已发展出快速且敏感的基因分型测定可在 30 分钟内检测到这些突变，以确保术中分子神经胶质瘤标本的诊断。第一个目标是建立基因分型测定作为临床测试的辅助手段用于术中诊断和围手术期监测。首先，在 Iafrate 博士和 Lennerz 博士的指导下，专门从事分子诊断的病理学家，候选人将学习 CLIA 认证的过程，以便建立所描述的基因分型测定作为临床测试。该测试将用于分析立体定向大脑与神经病理学家 Stemmer-Rachamimov 博士一起进行活检，以确定是否增强冰冻切片分析利用分子信息可以从早期的核心活检中获得病理诊断。在第二个目标中，候选人将与神经外科医生 Cahill 博士合作，从神经胶质瘤切除中获取边缘活检，以量化肿瘤使用基于 qPCR 的方法进行突变等位基因分数。然后将前瞻性地跟踪该队列，以将计算等位基因分数的肿瘤进展的时空风险概况；其结果可能是对辅助放射治疗现场规划的影响。第三个目标是前瞻性地采集血液样本在神经肿瘤学家 Batchelor 博士的支持下，在特定时间点从神经胶质瘤患者身上进行了研究。无细胞肿瘤将分析这些样本的 DNA 片段，以确定本检测中涵盖的复发热点突变。这液体活检中低丰度等位基因的检测具有挑战性，卡特博士的研究专业知识将指导候选人的技术方法。顺便说一句，BRAF 和 TERT 启动子突变在恶性细胞中非常普遍。黑色素瘤。因此，与黑色素瘤肿瘤学家沙利文博士合作，候选人将应用这种方法对从转移性黑色素瘤患者获得的血液样本进行纵向分析以评估治疗回复。总的来说，要检验的假设是，如果实体瘤的围手术期靶向突变分析标本和液体活检进一步建立病理诊断和治疗反应评估，分别提供这些信息的临床检测可以指导手术和辅助治疗决策。我们提出类似的方法可以类似地扩展到以明确突变为特征的其他实体瘤。