Development of next generation 2HG and metabolic MR imaging for precision oncology of mutant IDH and wildtype glioma patients

开发下一代 2HG 和代谢 MR 成像，用于突变 IDH 和野生型神经胶质瘤患者的精准肿瘤学

• 批准号: 10552040
• 负责人: Ovidiu C Andronesi
• 金额: $ 56.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552040
• 关键词: 3-Dimensional; Acceleration; Adult; Age; Agreement; Big Data; Biological Markers; Biopsy; Brain; Brain Neoplasms; Brain imaging; Cancer Etiology; Cancer Patient; Cessation of life; Classification; Clinical; Clinical Trials; Computer software; Data Analytics; Detection; Development; Diagnosis; Diffuse; Early Diagnosis; Enzymes; Epigenetic Process; Evaluation; Event; Gene Expression; Generations; Glioma; Goals; Growth; Image; Imaging Device; Immune response; Individual; Isocitrate Dehydrogenase; Joints; Knowledge; Life; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Metabolic; Methods; Mission; Modification; Molecular; Molecular Profiling; Monitor; Motion; Mutation; Noise; Oncogenic; Operative Surgical Procedures; Outcome; Pathology; Patient-Focused Outcomes; Patients; Performance; Persons; Primary Brain Neoplasms; Prognosis; Public Health; Quantitative Evaluations; Radiation; Research; Resolution; Sampling Biases; Scanning; Signal Transduction; Survival Rate; Testing; Therapeutic; Time; Translating; Tumor Burden; Tumor Promotion; Update; Vaccines; Work; analysis pipeline; artificial neural network; cancer imaging; cancer therapy; chemoradiation; chemotherapy; clinical phenotype; clinical translation; cost effective; data quality; deep learning; denoising; diagnostic tool; first-in-human; imaging agent; imaging biomarker; imaging modality; improved; improved outcome; in vivo; in vivo imaging; inhibitor; innovation; magnetic resonance spectroscopic imaging; metabolic imaging; molecular imaging; molecular marker; mutant; nervous system disorder; neuro-oncology; new therapeutic target; next generation; novel; patient population; precision oncology; reconstruction; response; success; targeted therapy trials; targeted treatment; tool; treatment planning; treatment response; tumor; usability; user-friendly

7. Project Summary/Abstract Gliomas are rarely curable tumors with a low survival rate of 36% at five-years that is well below the average survival rate of 67.2% across all cancers, according to SEER and CBTRUS. Malignant brain tumors cause an average of 20 years of potential life lost (YPLL) for individuals diagnosed as adults, which exceeds most common cancers. Survival and YPLL have not improved for gliomas similarly to other cancers and progress is desperately needed. The lack of improvement in patient outcomes is not due to lack of new discoveries, but due to limited success in translating this knowledge into clinical benefit. Important discoveries have been made over the last decade regarding key molecular mechanisms involved in glioma initiation and growth, which have been incorporated in the latest WHO classification. IDH mutation is the primary event in glioma initiation and has become a paradigm shift in the treatment of glioma. Neuro-oncology experts (SNO, EANO) agree that brain imaging can accelerate clinical trials of targeted therapies and mandated the development of molecular imaging for highly specific and sensitive glioma imaging. The long-term goal of our research is the development of non-invasive molecular imaging methods that can be used clinically in cancer patients. IDH mutations are frequent in glioma and produce high levels of the oncometabolite 2-hydroxyglutarate (2HG) that can be imaged as a biomarker for diagnosis, prognosis, prediction, guidance of surgery and radiation, response to chemotherapy and targeted treatments. The objective of this application is to develop fast high resolution whole brain quantitative 2HG and metabolic imaging for diagnosis, treatment guidance and monitoring of mutant IDH and wildtype glioma. The central hypothesis of our proposal is that advancing next generation 2HG and metabolic imaging will enable precision oncology and accelerate clinical translation of novel targeted therapies to improve outcomes in mutant IDH and wildtype glioma patients. Three specific aims will be performed for this: 1) develop fast high-resolution whole-brain clinically robust 2HG and metabolic imaging, 2) improve sensitivity, precision, accuracy and workflow of 2HG and metabolic imaging, and 3) clinical translation of next generation 2HG and metabolic imaging in glioma patients. There are strong rationales for the proposed research: 1) there is no alternative in vivo imaging method specific for IDH mutations, 2) 2HG imaging is completely non-invasive, can be repeated safe without any radiation, can provide results fast and cost effective, 3) provides comprehensive evaluation of the entire tumor and healthy brain without the sampling bias of biopsies, 4) it can be performed pre-surgically and in tumors that cannot be operated. The approach is innovative because it employs the first available whole brain 2HG imaging method, which will be accelerated by compressed sensing, novel shim hardware to improve data quality, and transformed in a high throughput automated tool by deep learning. The contribution of the proposed research will be significant because it will provide clinicians with a user-friendly and precise tool for diagnostic, guiding and monitoring of glioma patients.

7. 项目总结/摘要 神经胶质瘤是很少能治愈的肿瘤，五年生存率低至 36%，远低于平均水平 根据 SEER 和 CBTRUS 的数据，所有癌症的生存率为 67.2%。恶性脑肿瘤会导致 被诊断为成年人的个体平均潜在寿命损失 (YPLL) 为 20 年，超过了大多数人 常见癌症。与其他癌症类似，神经胶质瘤的生存率和 YPLL 并未得到改善，而且进展缓慢 迫切需要。患者治疗效果缺乏改善并不是因为缺乏新发现，而是因为 由于将这些知识转化为临床效益的成功有限。已有重要发现 在过去的十年中，关于神经胶质瘤发生和生长的关键分子机制， 已纳入最新的 WHO 分类。 IDH突变是神经胶质瘤发生和发展的主要事件 已成为神经胶质瘤治疗的范式转变。神经肿瘤学专家（SNO、EANO）一致认为 脑成像可以加速靶向治疗的临床试验，并强制开发分子疗法 用于高度特异性和敏感性神经胶质瘤成像的成像。我们研究的长期目标是 开发可临床用于癌症患者的非侵入性分子成像方法。异丁烯酸脱氢酶 突变在神经胶质瘤中很常见，并产生高水平的致癌代谢物 2-羟基戊二酸 (2HG)， 可以成像作为诊断、预后、预测、手术和放射指导的生物标志物， 对化疗和靶向治疗的反应。该应用程序的目标是快速开发高 分辨率全脑定量 2HG 和代谢成像，用于诊断、治疗指导和 突变 IDH 和野生型神经胶质瘤的监测。我们提案的中心假设是下一步推进 第二代HG和代谢成像将实现精准肿瘤学并加速临床转化 新型靶向疗法可改善突变 IDH 和野生型神经胶质瘤患者的预后。三个具体目标 为此将进行：1）开发快速高分辨率全脑临床稳健的2HG和代谢 成像，2) 提高 2HG 和代谢成像的灵敏度、精确度、准确性和工作流程，以及 3) 临床 下一代 2HG 和代谢成像在神经胶质瘤患者中的转化。有充分的理由 拟议的研究：1) 没有针对 IDH 突变的替代体内成像方法，2) 2HG 成像是完全非侵入性的，可以在没有任何辐射的情况下安全地重复，可以快速提供结果 成本效益高，3）无需采样即可对整个肿瘤和健康大脑进行全面评估 活检的偏差，4) 可以在手术前和无法手术的肿瘤中进行。方法是 创新之处在于它采用了第一个可用的全脑 2HG 成像方法，该方法将加速 通过压缩感知、新颖的垫片硬件来提高数据质量，并以高吞吐量进行转化 深度学习的自动化工具。拟议研究的贡献将是重大的，因为它将 为临床医生提供用户友好且精确的工具来诊断、指导和监测神经胶质瘤患者。