Blood-based biomarker amplification using high intensity focused ultrasound (HIFU

使用高强度聚焦超声 (HIFU) 进行基于血液的生物标志物扩增

• 批准号: 8351837
• 负责人: Tatiana Khokhlova
• 金额: $ 14.45万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8351837
• 关键词: Ablation; Acoustics; Acute; Affect; Animal Model; Animals; Area; Articular Range of Motion; Award; Benign; Benign Prostatic Hypertrophy; Biological Markers; Biopsy; Biotechnology; Blood; Blood Circulation; Blood flow; Blood specimen; Cancer Patient; Cardiac; Cells; Clinic; Collaborations; Cytolysis; Detection; Development; Devices; Diagnosis; Dimensions; Disease; Doctor of Philosophy; Elderly man; Engineering; Environment; Explosion; Extracellular Space; Failure; Focused Ultrasound Therapy; Fred Hutchinson Cancer Research Center; Frequencies; Furuncles; Gel; Goals; Heat-Shock Response; Heating; Heterogeneity; Histocompatibility Testing; Hour; Human; Individual; Infection; Internal Medicine; K-Series Research Career Programs; Laboratories; Lead; Length; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Mechanics; Medical; Medical Technology; Medicine; Mentors; Methods; Metric; MicroRNAs; Microbiology; Monitor; Morbidity - disease rate; Motion; Nature; Outcome; Output; Pancreas; Patients; Pediatric Hospitals; Physics; Physiologic pulse; Plasma; Procedures; Prostate; Prostate-Specific Antigen; Protocols documentation; Public Health; Relative (related person); Reporting; Research; Research Personnel; Risk; Sampling; Scheme; Scientist; Screening procedure; Serum; Shock; Source; Techniques; Technology; Temperature; Testing; Time; Tissue Sample; Tissues; Translating; Tumor Tissue; Ultrasonic Therapy; Ultrasonography; Ultrasound, High-Intensity Focused, Transrectal; Universities; Washington; Water; Work; absorption; base; cancer classification; cancer diagnosis; clinical application; clinically relevant; cost; design; heat injury; improved; in vivo; in vivo Model; interest; medical schools; millisecond; novel; novel therapeutics; rectal; respiratory; therapy design; tool; tumor

DESCRIPTION (provided by applicant): Benign prostate hyperplasia (BPH) and prostate cancer are very common prostate conditions in elderly men, and current non-invasive screening tools, e.g., Prostate Specific Antigen (PSA) tests, often fail to differentiate between the two. Ths failure leads to extensive use of prostate biopsies to obtain tissue samples for histological examination. Not only is this procedure uncomfortable, unpleasant and prone to complications, the rate of false negatives is high due to the multifocal nature of prostate cancer. Development of reliable blood-based biomarkers for prostate cancer would eliminate the need for invasive biopsies, but still remains an unmet challenge. Recently a class of small regulatory RNAs - micro-RNAs - has shown great promise as a blood-based biomarker for prostate cancer diagnosis and prognostication. However, according to the studies reported to date, the sensitivity of this technique is too low to be clinically relevant. High intensity focused ultrasoud (HIFU) therapy is a non-invasive ablation method, in which ultrasound energy from an extracorporeal or trans-rectal source can be focused within the body to induce thermal denaturation of tissue at the focus without affecting surrounding tissues. A novel type of HIFU exposure designed for inducing purely mechanical erosion of tissue, viz., histotripsy, was recently proposed. This type of exposure utilizes highly nonlinear short HIFU pulses to induce localized boiling at the focus in as fast as a few milliseconds. Erosive damage to tissue is produced by the explosion of the resulting boiling bubble and its interaction with the HIFU field. The ultimate goal of this proposal is to use HIFU for localized targeted lysis of selected areas of the prostate that will lead to the release of cell contents into the extracellular space and increae the concentration of tissue-specific micro-RNAs in the circulation. Thus, the sensitivity of micro-RNA-based tests for diagnosis of prostate conditions will be significantly enhanced. This combined technique may thus be termed "non-invasive biopsy". The Specific Aims of this proposal are: 1) characterize high amplitude, nonlinear acoustic outputs of the HIFU sources relevant to trans-rectal applications, 2) observe the erosive effect produced by HIFU in transparent tissue-mimicking gel phantoms and 3) ex-vivo tissue with different pulsing protocols, 4) optimize and apply HIFU exposures causing localized tissue lysis in a small animal tumor model in-vivo and 5) determine if the concentration of tumor-specific micro-RNAs in the circulation is enhanced following HIFU- induced localized tumor lysis in a small animal model. The long-term research goal of the candidate applying for this Career Development Award (Tatiana Khokhlova, PhD) is to optimize this non-invasive biopsy technique, transform the corresponding HIFU device to work trans-rectally, and translate the concept into a clinically useful approach to perform non-invasive biopsy of the prostate. The research environment at the University of Washington that includes experts in medical ultrasound (Applied Physics Laboratory, Center for Industrial and Medical Ultrasound), microbiology (Fred Hutchinson Cancer Research Center) and medicine (School of Medicine) is perfect for achieving this goal. Dr. Khokhlova is an ultrasound physicist and engineer, and has worked extensively in the field of medical applications of ultrasound technology. This interdisciplinary background enables Dr. Khokhlova to successfully collaborate with both clinicians and scientists. Dr. Khokhlova plans to pursue research in novel therapeutic ultrasound technologies, to continue current collaborations with the Fred Hutchinson Cancer Research Center and Children's Hospital, and thus be connected with both scientists and clinicians and facilitate more rapid transfer of the exciting new developments in medical ultrasound directly into the clinic. The primary reason for applying for this Award is to permit Dr. Khokhlova to gain further expertise in biotechnology and internal medicine and to develop into an independent investigator while being mentored by three highly successful researchers, Drs. Joo Ha Hwang, Lawrence Crum, and Muneesh Tewari. PUBLIC HEALTH RELEVANCE: Micro-RNAs are a promising class of blood-based biomarkers for the diagnosis of benign and malignant prostate conditions, however, to date these tests lack sensitivity. High Intensity Focused Ultrasound (HIFU) can induce localized, targeted and non-invasive lysis of suspicious areas of the prostate, which will lead to the release of micro-RNAs into the circulation, and thus facilitate tumor-specific micro-RNA detection in a blood sample. This study will benefit public health by improving the accuracy of prostate condition diagnosis and decreasing the cost and morbidity of the associated procedure; furthermore, once this approach is shown to be successful in the prostate, its broad application to a number of other diseases is probable.

描述（由申请人提供）：良性前列腺增生（BPH）和前列腺癌是老年男性中非常常见的前列腺疾病，目前的非侵入性筛查工具，例如前列腺特异性抗原（PSA）测试，通常无法区分这两种疾病。这种失败导致广泛使用前列腺活检来获取组织样本进行组织学检查。该手术不仅不舒服、不愉快且容易出现并发症，而且由于前列腺癌的多灶性，假阴性率很高。开发可靠的前列腺癌血液生物标志物将消除侵入性活检的需要，但仍然是一个尚未解决的挑战。最近，一类小调节 RNA（微小 RNA）作为前列腺癌诊断和预测的血液生物标志物显示出了巨大的前景。然而，根据迄今为止报道的研究，该技术的敏感性太低，不具有临床意义。高强度聚焦超声（HIFU）治疗是一种非侵入性消融方法，其中来自体外或经直肠源的超声能量可以在体内聚焦以引起病灶处组织的热变性而不影响周围组织。最近提出了一种新型的 HIFU 暴露，旨在诱导组织的纯机械侵蚀，即组织解剖术。这种类型的曝光利用高度非线性的短 HIFU 脉冲在焦点处引发局部沸腾，速度快至几毫秒。所产生的沸腾气泡的爆炸及其与 HIFU 场的相互作用会对组织造成侵蚀性损伤。该提案的最终目标是使用 HIFU 对选定区域进行局部靶向裂解。 前列腺，这将导致细胞内容物释放到细胞外空间，并增加循环中组织特异性 micro-RNA 的浓度。因此，基于微小RNA的测试诊断前列腺疾病的敏感性将显着增强。这种组合技术因此可以被称为“非侵入性活检”。该提案的具体目标是：1）表征与经直肠应用相关的 HIFU 源的高振幅、非线性声输出，2）观察 HIFU 在透明组织模拟凝胶体模中产生的侵蚀效应，3）体外组织具有不同的脉冲方案，4) 优化并应用 HIFU 暴露，在体内小动物肿瘤模型中引起局部组织溶解，5) 确定是否在小动物模型中，HIFU 诱导局部肿瘤溶解后，循环中的肿瘤特异性 micro-RNA 得到增强。申请该职业发展奖的候选人（Tatiana Khokhlova，博士）的长期研究目标是优化这种无创活检技术，将相应的HIFU设备改造为经直肠工作，并将这一概念转化为临床有用的技术。一种对前列腺进行非侵入性活检的方法。华盛顿大学的研究环境包括医学超声（应用物理实验室、工业和医学超声中心）、微生物学（弗雷德哈钦森癌症研究中心）和医学（医学院）专家，非常适合实现这一目标。 Khokhlova 博士是一位超声物理学家和工程师，在超声技术的医疗应用领域有着广泛的工作。这种跨学科背景使 Khokhlova 博士能够与临床医生和科学家成功合作。 Khokhlova 博士计划继续研究新型超声治疗技术，继续与 Fred Hutchinson 癌症研究中心和儿童医院目前的合作，从而与科学家和临床医生建立联系，并促进更快速地传播医学超声领域令人兴奋的新发展直接进入诊所。申请该奖项的主要原因是让 Khokhlova 博士能够获得生物技术和内科方面的进一步专业知识，并在三位非常成功的研究人员 Drs. Drs. 的指导下发展成为一名独立研究者。朱河黄、劳伦斯·克拉姆和穆尼什·特瓦里。 公共健康相关性：微小 RNA 是一类很有前途的血液生物标志物，可用于诊断良性和恶性前列腺疾病，但迄今为止，这些测试缺乏敏感性。高强度聚焦超声（HIFU）可以诱导前列腺可疑区域的局部、靶向和非侵入性裂解，从而导致微小RNA释放到循环中，从而促进肿瘤特异性微小RNA的检测。血液样本。这项研究将通过提高前列腺疾病诊断的准确性并降低相关手术的成本和发病率来造福公众健康；此外，一旦证明这种方法在前列腺治疗中取得成功，它就有可能广泛应用于许多其他疾病。