Integrating circulating tumor DNA assay and protein-based MRI to accurately monitor glioma therapy

整合循环肿瘤 DNA 检测和基于蛋白质的 MRI 来准确监测神经胶质瘤治疗

• 批准号: 10735404
• 负责人: CHETAN BETTEGOWDA
• 金额: $ 69.14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735404
• 关键词: Aftercare; Amides; Aneuploidy; Attention; Bioinformatics; Biological Assay; Biological Markers; Biopsy; Cells; Cerebrospinal Fluid; Characteristics; Clinical; Complex; Correlation Studies; DNA; DNA analysis; Data; Diagnostic; Disease; FDA approved; Genetic Markers; Genetic Status; Genomics; Genotype; Glioblastoma; Glioma; Goals; Heterogeneity; Human; Image; Individual; Investigation; Longitudinal Studies; MGMT gene; MRI Scans; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Methods; Modality; Modeling; Molecular; Monitor; Mutation; Names; Neurosurgical Procedures; Newly Diagnosed; Operative Surgical Procedures; Outcome; Patient Care; Patients; Pattern; Phenotype; Plasma; Primary Brain Neoplasms; Prognosis; Progression-Free Survivals; Proteins; Protocols documentation; Protons; Recurrence; Recurrent disease; Recurrent tumor; Reporting; Risk; Sampling; Signal Transduction; Somatic Mutation; Techniques; Text; Time; Tissue Sample; Tissues; Tumor Burden; Tumor Tissue; Tumor-Derived; burden of illness; chemoradiation; deep learning; deep learning model; diagnostic strategy; improved; indexing; liquid biopsy; minimally invasive; molecular imaging; multimodality; neurosurgery; novel; predictive modeling; prognostic; radiomics; recruit; response; standard care; success; temozolomide; tool; treatment effect; treatment response; tumor; tumor DNA; tumor progression

SUMMARY Glioblastoma is the most common primary brain tumor with substantial genomic, molecular and phenotypic heterogeneity, but uniformly dismal outcomes despite the current standard treatment of concurrent temozolomide chemo-radiotherapy (CRT). Given the pace of disease recurrence and the challenges associated with obtaining tumor tissue, there is an unmet clinical need for the real-time, noninvasive assessment of GBM responsiveness to CRT. As demonstrated previously, most cancers shed tumor-derived fragmented DNA into biofluids, including plasma and cerebrospinal fluid (CSF), and these cell-free molecules can be quantified as a measure of disease burden. The approach, named “liquid biopsy”, has recently emerged as a breakthrough diagnostic and monitoring tool for diseases such as cancer, with the added benefit of being minimally invasive. Through the sampling and analysis of biofluids, a number of promising glioma biomarkers, derived from tumor-derived DNA in plasma (ctDNA) and CSF (CSF-tDNA) (together called rtDNA), have been reported as diagnostic strategies for gliomas. Meanwhile, numerous previous studies have demonstrated that protein-based amide proton transfer (APT) MRI can accurately identify tumor burden and genetic markers (such as IDH, MGMT status) in gliomas. The goals of this proposal are to combine ctDNA and CSF-tDNA with APT MRI to resolve the diagnostic challenges associated with discriminating treatment effect from tumor progression and to develop an efficient and reliable deep-learning framework for post-treatment monitoring. We propose the following specific aims to be performed: (1) correlate ctDNA and CSF-tDNA levels with protein-based APT MRI characteristics when monitoring GBM treated with CRT; (2) determine the accuracy of combined rtDNA/APT indices in identifying GBM recurrence; and (3) develop a transformer pipeline using rtDNA and mpMRI to assess GBM prognosis. The success of this aim will help to understand the dynamic patterns of rtDNA/APT throughout the treatment course for individuals with GBM. If our rtDNA/APT investigation is successful, the results would dramatically improve the care of patients treated with CRT and spare many patients from undergoing surgery for diagnostic purposes.

概括 胶质母细胞瘤是最常见的原发性脑肿瘤，具有大量的基因组，分子和表型 异质性，但统一的结果目的地目前的标准治疗 替莫唑胺化学疗法（CRT）。鉴于疾病复发的速度和挑战 与获得肿瘤组织有关，对实时无创的临床需求未满足 评估GBM对CRT的响应能力。如前所述，大多数癌症脱落了肿瘤的衍生 分散的DNA成生物流体，包括血浆和脑脊液（CSF），以及这些无细胞的分子 可以量化为伯恩疾病的量度。该方法被称为“液体活检”，最近有了 成为癌症等疾病的突破性诊断和监测工具，并带来额外的好处 最少的侵入性。通过对生物流体的采样和分析，许多有望的神经胶质瘤 生物标志物，源自血浆（CTDNA）和CSF（CSF-TDNA）（称为rtDNA）的肿瘤衍生的DNA，称为rtDNA）， 已报告是胶质瘤的诊断策略。同时，许多先前的研究已经 证明基于蛋白质的酰胺质子转移（APT）MRI可以准确识别肿瘤伯嫩和 胶质瘤中的遗传标记（例如IDH，MGMT状态）。该提案的目标是结合ctDNA和 CSF-TDNA具有APT MRI，以解决与歧视治疗效果相关的诊断挑战 从肿瘤的进展，发展一个有效且可靠的深度学习框架以进行后处理 监视。我们提出以下特定目标：（1）相关的ctDNA和CSF-TDNA水平 当监测用CRT处理的GBM时，具有基于蛋白质的APT MRI特性； （2）确定 识别GBM复发方面的RTDNA/APT指数的准确性； （3）开发变压器 使用rtDNA和mpMRI评估GBM预后的管道。这个目标的成功将有助于理解 在整个治疗过程中，RTDNA/APT的动态模式针对患有GBM的个体。如果我们 RTDNA/APT调查成功，结果将大大改善接受治疗的患者的护理 CRT和许多患者出于诊断目的进行手术。