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.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Scientist Development Award - Research & Training (K01)
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Special Emphasis Panel (ZEB1-OSR-B (M2))
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Erim, Zeynep
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Chevillet, John R; Khokhlova, Tatiana D; Giraldez, Maria D et al. (2017) Release of Cell-free MicroRNA Tumor Biomarkers into the Blood Circulation with Pulsed Focused Ultrasound: A Noninvasive, Anatomically Localized, Molecular Liquid Biopsy. Radiology 283:158-167
Maxwell, Adam D; Yuldashev, Petr V; Kreider, Wayne et al. (2017) A Prototype Therapy System for Transcutaneous Application of Boiling Histotripsy. IEEE Trans Ultrason Ferroelectr Freq Control 64:1542-1557
Khokhlova, Tatiana D; Haider, Yasser A; Maxwell, Adam D et al. (2017) Dependence of Boiling Histotripsy Treatment Efficiency on HIFU Frequency and Focal Pressure Levels. Ultrasound Med Biol 43:1975-1985
Khokhlova, Tatiana D; Monsky, Wayne L; Haider, Yasser A et al. (2016) Histotripsy Liquefaction of Large Hematomas. Ultrasound Med Biol 42:1491-8
Li, Tong; Wang, Yak-Nam; Khokhlova, Tatiana D et al. (2015) Pulsed High-Intensity Focused Ultrasound Enhances Delivery of Doxorubicin in a Preclinical Model of Pancreatic Cancer. Cancer Res 75:3738-46
Li, Tong; Khokhlova, Tatiana; Maloney, Ezekiel et al. (2015) Endoscopic high-intensity focused US: technical aspects and studies in an in vivo porcine model (with video). Gastrointest Endosc 81:1243-50
Khokhlova, Tatiana D; Haider, Yasser; Hwang, Joo Ha (2015) Therapeutic potential of ultrasound microbubbles in gastrointestinal oncology: recent advances and future prospects. Therap Adv Gastroenterol 8:384-94
Khokhlova, Vera A; Fowlkes, J Brian; Roberts, William W et al. (2015) Histotripsy methods in mechanical disintegration of tissue: towards clinical applications. Int J Hyperthermia 31:145-62
Khokhlova, Tatiana D; Wang, Yak-Nam; Simon, Julianna C et al. (2014) Ultrasound-guided tissue fractionation by high intensity focused ultrasound in an in vivo porcine liver model. Proc Natl Acad Sci U S A 111:8161-6
Li, Tong; Chen, Hong; Khokhlova, Tatiana et al. (2014) Passive cavitation detection during pulsed HIFU exposures of ex vivo tissues and in vivo mouse pancreatic tumors. Ultrasound Med Biol 40:1523-34

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