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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01EB015745-01
Application #
8351837
Study Section
Special Emphasis Panel (ZEB1-OSR-B (M2))
Program Officer
Erim, Zeynep
Project Start
2012-08-01
Project End
2017-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$144,456
Indirect Cost
$10,700
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Li, Tong; Khokhlova, Tatiana D; Sapozhnikov, Oleg A et al. (2014) A new active cavitation mapping technique for pulsed HIFU applications--bubble Doppler. IEEE Trans Ultrason Ferroelectr Freq Control 61:1698-708
Poliachik, Sandra L; Khokhlova, Tatiana D; Wang, Yak-Nam et al. (2014) Pulsed focused ultrasound treatment of muscle mitigates paralysis-induced bone loss in the adjacent bone: a study in a mouse model. Ultrasound Med Biol 40:2113-24
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
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
Wang, Yak-Nam; Khokhlova, Tatiana; Bailey, Michael et al. (2013) Histological and biochemical analysis of mechanical and thermal bioeffects in boiling histotripsy lesions induced by high intensity focused ultrasound. Ultrasound Med Biol 39:424-38