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

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非常常见的前列腺疾病，目前的非侵入性筛查工具，如前列腺特异性抗原（PSA）测试，往往无法区分这两者。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。这个过程不仅不舒服，不愉快，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。开发可靠的基于血液的前列腺癌生物标志物将消除侵入性活检的需要，但仍然是一个未解决的挑战。最近，一类小的调控rna——微rna——作为一种基于血液的前列腺癌诊断和预后的生物标志物显示出了巨大的希望。然而，根据迄今为止报道的研究，该技术的敏感性太低，无法与临床相关。高强度聚焦超声（HIFU）治疗是一种非侵入性消融方法，通过体外或经直肠源的超声能量在体内聚焦，在不影响周围组织的情况下诱导病灶组织热变性。最近提出了一种新型的HIFU暴露，用于诱导纯机械组织侵蚀，即组织切片。这种类型的曝光利用高度非线性的短HIFU脉冲在几毫秒内诱导焦点处的局部沸腾。对组织的侵蚀性损伤是由沸腾气泡的爆炸及其与HIFU场的相互作用产生的。本提案的最终目标是使用HIFU对选定的区域进行局部靶向裂解

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.