MRgFUS-enabled non-invasive interrogation of malignant glioma via circulating tumor DNA
MRgFUS-enabled non-invasive interrogation of malignant glioma via circulating tumor DNA
批准号:
9808152
负责人:
CHETAN BETTEGOWDA
金额:
$45.35万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-07-15 至 2023-06-30
关键词:
AddressAdultAnimal ModelAnimalsBiopsyBloodBlood - brain barrier anatomyBlood CirculationBrainBrain InjuriesBrain NeoplasmsCancer PatientCerebrospinal FluidChromosome DeletionChromosome abnormalityClinicalClinical DataClinical ManagementClinical TrialsCollaborationsDNADNA Sequence AlterationDNA sequencingDeletion MutationDetectionDevelopmentDiagnosisDiagnosticEnrollmentFDA approvedFocused UltrasoundGene MutationGlioblastomaGliomaHumanInstitutional Review BoardsLeadLesionLocationMagnetic Resonance ImagingMalignant GliomaMalignant neoplasm of brainMediatingMicrobubblesModelingMolecularMolecular DiagnosisMolecular ProfilingMonitorNeoplasmsNerve DegenerationNeuraxisNon-Invasive Cancer DetectionPatientsRattusRecording of previous eventsResearchResistanceRodentSafetyScientistSolid NeoplasmSpecimenStreamTechniquesTechnologyTestingUltrasonic TherapyUltrasonographyWorkanticancer researchbrain tissueclinical implementationclinical translationcraniumhuman diseasehuman modelimage guidedimprovedinjuredliquid biopsypre-clinicalpublic health relevancetumortumor DNA
中文摘要
项目摘要
染色体缺失和DNA突变的分子指纹图谱在临床上越来越重要
胶质母细胞瘤(GBM)是最常见和最致命的成人原发脑肿瘤。
虽然到目前为止,对肿瘤DNA的临床分析依赖于神经外科标本,但非侵入性
通过液体活检检测循环肿瘤dna(Ctdna)具有使检测发生革命性变化的潜力。
以及对这些侵袭性、异质性和治疗耐药肿瘤的监测。尽管有几个
研究小组在非中枢神经系统(CNS)肿瘤患者的保护位置检测到了ctDNA
中枢神经系统内的脑瘤可能会限制ctdna等分子通过血脑屏障。
(Bbb)。一种新的非侵入性破坏血脑屏障的技术是磁共振成像引导聚焦
超声(MRgFUS)。MRgFUS可以安全、高精度地将超声能量传递到完整的颅骨
和准确性,并被FDA批准用于治疗某些神经退行性疾病使用高能量
热力调节。MRgFUS介导的BBB中断是在相对较低的能量设置下完成的,
被用来振荡循环微泡,扰乱和暂时扰乱血脑屏障。项目团队
正在领导研究MRgFUS介导的脑癌患者血脑屏障中断的美国临床试验,以及
在实体瘤环境中敏感和特异地检测ctDNA方面一直是先驱。因此,
我们建议研究MRgFUS,通过肿瘤的中枢神经系统外释放,实现脑癌的液体活检
DNA我们的总体假设是,使用MRgFUS将血脑屏障干扰定位于特定的脑肿瘤区域
将肿瘤区域特异性DNA释放到循环中,这种ctDNA将被检测到使用我们高度敏感的
DNA测序技术。我们进一步预测,超声设置可以进一步调整和优化
保持安全性并增加ctDNA的释放,以提高检测/诊断效率。我们将对此进行测试
两个特定目标的假设:在目标1中,我们将研究FUS触发的胶质瘤释放的动力学。
将DNA注入先进的临床前GBM大鼠模型的血流中,并确定最佳设置
以及肿瘤DNA释放的时机,同时保持安全。在目标2中,我们建议评估是否存在
脑肿瘤患者血液中肿瘤特异性DNA的变化
由我们团队领导的临床试验。成功完成了与建立MRgFUS的潜力的工作
能够对基底膜进行非侵入性活组织检查,这将从根本上提高对人类
脑癌。
英文摘要
Project Summary
Molecular fingerprinting of chromosomal deletions and DNA mutations is increasingly important in the clinical
management of patients with glioblastoma (GBM) – the most common and deadly primary adult brain tumor.
While clinical analyses of tumor DNA have to this point relied on neurosurgical specimens, non-invasive
detection through liquid biopsy of circulating tumor DNA (ctDNA) has the potential to revolutionize the detection
and monitoring of these aggressive, heterogeneous, and treatment resistant neoplasms. Although several
groups have detected ctDNA in patients with non-central nervous system (CNS) tumors, the protected location
of brain tumors within the CNS likely limits the passage of molecules like ctDNA through the blood brain barrier
(BBB). A new non-invasive technology to disrupt the BBB is magnetic resonance imaging-guided focused
ultrasound (MRgFUS). MRgFUS can safely deliver ultrasound energy across the intact skull with high precision
and accuracy, and is FDA-approved for the treatment of certain neurodegenerative conditions using high energy
thermal lesioning. MRgFUS-mediated BBB disruption is accomplished with relatively low energy settings which
are used to oscillate circulating microbubbles, perturbing and temporarily disrupting the BBB. The project team
is leading the US clinical trials investigating MRgFUS-mediated BBB disruption in brain cancer patients, and
have been pioneers in the sensitive and specific detection of ctDNA in the setting of solid tumors. Accordingly,
we propose investigating MRgFUS to enable liquid biopsy of brain cancer through extra-CNS release of tumor
DNA. Our overall hypothesis is that BBB disruption localized to specific brain tumor regions using MRgFUS will
release tumor region-specific DNA into the circulation and this ctDNA will be detectable using our highly sensitive
DNA sequencing technology. We further predict that the ultrasound settings can be further tuned and optimized
to maintain safety and increase release of ctDNA to improve detection/diagnostic yield. We will test this
hypothesis in two specific aims: In Aim 1, we will investigate the dynamics of FUS-triggered release of glioma
DNA into the blood stream in advanced, faithful pre-clinical GBM rat models and determine the optimal settings
and timing of tumor DNA release while maintaining safety. In Aim 2, we propose to assess the presence of
tumor-specific DNA in the blood of brain tumor patients who will be already enrolled in MRgFUS-mediated BBBD
clinical trials lead by our team. Successful completion of the work with establish the potential for MRgFUS
enabled, non-invasive biopsy of GBM, which would radically advance the diagnosis and monitoring of human
brain cancer.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Integrating circulating tumor DNA assay and protein-based MRI to accurately monitor glioma therapy
-
批准号:10735404
-
项目类别:
-
资助金额:$69.14万
-
财政年份:2023
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
Cell-free DNA-Based Analysis for Diagnosis, Monitoring and Optimization of Therapy for Patients with Primary Central Nervous System Lymphomas
-
批准号:10705063
-
项目类别:
-
资助金额:$24.56万
-
财政年份:2022
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
Cell-free DNA-Based Analysis for Diagnosis, Monitoring and Optimization of Therapy for Patients with Primary Central Nervous System Lymphomas
-
批准号:10420404
-
项目类别:
-
资助金额:$20.47万
-
财政年份:2022
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
Validation of Biomarkers for predicting Barrett's esophagus that will or will not: i) progress towards cancer, or ii) recur after ablation
-
批准号:10708890
-
项目类别:
-
资助金额:$102.83万
-
财政年份:2022
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
Phase IIA Trial of Dichloroacetate for Glioblastoma Multiforme, IND137007, 09172019
-
批准号:10491763
-
项目类别:
-
资助金额:$65.97万
-
财政年份:2021
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
Phase IIA Trial of Dichloroacetate for Glioblastoma Multiforme, IND137007, 09172019
-
批准号:10693209
-
项目类别:
-
资助金额:$66.04万
-
财政年份:2021
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
Phase IIA Trial of Dichloroacetate for Glioblastoma Multiforme, IND137007, 09172019
-
批准号:10281354
-
项目类别:
-
资助金额:$54.16万
-
财政年份:2021
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
Earlier Detection of Cancers using Non-Plasma Based Liquid Biopsies
-
批准号:10474330
-
项目类别:
-
资助金额:$72.12万
-
财政年份:2018
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
Earlier Detection of Cancers using Non-Plasma Based Liquid Biopsies
-
批准号:9788317
-
项目类别:
-
资助金额:$71.44万
-
财政年份:2018
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
Interrogating malignant gliomas using released tumor DNA in cerebrospinal fluid
-
批准号:10208816
-
项目类别:
-
资助金额:$37.46万
-
财政年份:2018
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
Interrogating malignant gliomas using released tumor DNA in cerebrospinal fluid
-
批准号:10445048
-
项目类别:
-
资助金额:$37.46万
-
财政年份:2018
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
Interrogating malignant gliomas using released tumor DNA in cerebrospinal fluid
-
批准号:10610117
-
项目类别:
-
资助金额:$36.71万
-
财政年份:2018
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
(PQ 6) Exploiting Frequent Alterations in the PRC2 Complex to Distinguish Benign Neurofibromas from Malignant Peripheral Nerve Sheath Tumors
-
批准号:9334790
-
项目类别:
-
资助金额:$17.79万
-
财政年份:2016
-
负责人:CHETAN BETTEGOWDA
-
依托单位:
海外基金