Release of Cell-free MicroRNA Tumor Biomarkers into the Blood Circulation with Pulsed Focused Ultrasound: A Noninvasive, Anatomically Localized, Molecular Liquid Biopsy

Chevillet, John R.; Khokhlova, Tatiana D.; Giraldez, María D.; Schade, George R.; Starr, Frank; Wang, Yak Nam; Gallichotte, Emily N.; Wang, Kai; Hwang, Joo Ha; Tewari, Muneesh

doi:10.1148/radiol.2016160024

Cited by 39 publications

(25 citation statements)

References 34 publications

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“…We have shown that an increase in cell death increases biomarker-release [ 6 ] and therefore the use of MRg-FUS for ablation could allow for higher amplification of biomarker levels in humans, where the dilution of the biomarker in a large blood volume may limit detection. Recently, a systematic preclinical study from the authors has shown that both cavitation and liquefaction after pulsed focused sonication of tumors in rats can cause an increase in microRNA (miRNA) levels in plasma [ 14 ]. MRg-FUS has been shown to be safe in the use of tumor eradication and control of tumor growth by an increase in anti-tumor immune responses in several clinical and preclinical studies ([ 10 , 14 ]).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a systematic preclinical study from the authors has shown that both cavitation and liquefaction after pulsed focused sonication of tumors in rats can cause an increase in microRNA (miRNA) levels in plasma [ 14 ]. MRg-FUS has been shown to be safe in the use of tumor eradication and control of tumor growth by an increase in anti-tumor immune responses in several clinical and preclinical studies ([ 10 , 14 ]). The study of the use of MRg-FUS for the release of biomarkers from the benign human fibroids will guide us in the adaptation of the system for use in tumor biomarker release and localization at lower non-ablating ultrasound depositions.…”

Section: Introductionmentioning

confidence: 99%

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Tumor characterization by ultrasound-release of multiple protein and microRNA biomarkers, preclinical and clinical evidence

et al. 2018

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We have previously shown that low frequency ultrasound can release biomarkers from cells into the murine circulation enabling an amplification and localization of the released biomarker that could be used as a blood-based method to detect cancer earlier and monitor therapy. In this study, we further demonstrate that this technique could be used for characterization of tumors and/or identification of cellular masses of unknown origin due to the release of multiple protein and nucleic acid biomarkers in cells in culture, mice and patients. We sonicated colon (LS174T) and prostate (LNCaP) cancer cell lines in culture at a low frequency of 1 MHz and show that there were several-fold changes in multiple protein and microRNA (miRNA) abundance with treatment at various intensities and time. This release was dependent on the duration and intensity of the sonication for both cell lines. Significant increased release in biomarkers was also observed following tumor sonication in living mice bearing subcutaneous LS174T cell line xenografts (for proteins and nucleic acids) and in an experimental LS174T liver tumor model (for proteins only). Finally, we demonstrated this methodology of multiple biomarker release in patients undergoing ablation of uterine fibroids using MR guided high intensity focused ultrasound. Two protein biomarkers significantly increased in the plasma after the ultrasound treatment in 21 samples tested. This proof that ultrasound-amplification method works in soft tissue tumor models together with biomarker multiplexing, could allow for an effective non-invasive method for identification, characterization and localization of incidental lesions, cancer and other disease. Pre-treatment quantification of the biomarkers, allows for individualization of quantitative comparisons. This individualization of normal marker levels in this method allows for specificity of the biomarker-increase to each patient, tumor or organ being studied.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tumor characterization by ultrasound-release of multiple protein and microRNA biomarkers, preclinical and clinical evidence

et al. 2018

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“…Currently, mechanical HIFU technology, as applied to prostate ablation, is predominately at the phase of preclinical animal studies . In the very first study in humans, prostate hypertrophy was treated by the cavitation histotripsy technique in 25 patients with an extracorporeal HIFU device (Vortx Rx [Histosonics, Inc, Ann Arbor, MI]) .…”

Section: Thermal Versus Mechanical Hifumentioning

confidence: 99%

Histotripsy: The Next Generation of High‐Intensity Focused Ultrasound for Focal Prostate Cancer Therapy

Dubinsky

Khokhlova

et al. 2019

J of Ultrasound Medicine

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This article reviews the most current methods and technological aspects of highintensity focused ultrasound (HIFU), which is termed histotripsy. The rationale for focal therapy for prostate carcinoma rather than prostatectomy, which is being used extensively throughout Europe and Asia, is presented, and an argument for why HIFU is the modality of choice for primary therapy and recurrent disease is offered. The article presents a review of the technical advances including higher ultrasound beam energy than current thermal HIFU which allows for more accurate tissue targeting, less collateral tissue damage, and faster treatment times. Finally, the article presents a discussion about the advantage of ultrasound guidance for histotripsy in preference to magnetic resonance imaging guidance primarily based on cost, ease of application, and portability.

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“…Building on this initial work, in vitro cell culture studies showed the feasibility of enhancing mRNA biomarker release from a breast cancer cell line using microbubble-enhanced ultrasound 11 , and the feasibility of releasing a combination of ovarian cancer biomarkers using ultrasound 12 . Two recent in vivo studies further demonstrated that ultrasound-mediated release of biomarkers into the bloodstream is a promising approach for detecting tumor biomarkers via blood sampling 13 , 14 . In one of the studies, pulsed HIFU with high acoustic pressures was used to induce histotripsy ( i.e.…”

Section: Introductionmentioning

confidence: 99%

“…In one of the studies, pulsed HIFU with high acoustic pressures was used to induce histotripsy ( i.e. , a technique for mechanical tissue fractionation) in a rat model of prostate cancer, and this enhanced release of cell-free tumor microRNA into the blood circulation 13 . In the other study, a chicken embryo tumor model was used to show the feasibility of amplifying the release of extracellular vesicles using high-intensity focused ultrasound (HIFU) in combination with phase-change nanodroplets which changed to microbubbles upon HIFU sonication 14 .…”

Section: Introductionmentioning

confidence: 99%

Focused Ultrasound-enabled Brain Tumor Liquid Biopsy

Zhu

Cheng

et al. 2018

Sci Rep

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Although blood-based liquid biopsies have emerged as a promising non-invasive method to detect biomarkers in various cancers, limited progress has been made for brain tumors. One major obstacle is the blood-brain barrier (BBB), which hinders efficient passage of tumor biomarkers into the peripheral circulation. The objective of this study was to determine whether FUS in combination with microbubbles can enhance the release of biomarkers from the brain tumor to the blood circulation. Two glioblastoma tumor models (U87 and GL261), developed by intracranial injection of respective enhanced green fluorescent protein (eGFP)-transduced glioblastoma cells, were treated by FUS in the presence of systemically injected microbubbles. Effect of FUS on plasma eGFP mRNA levels was determined using quantitative polymerase chain reaction. eGFP mRNA were only detectable in the FUS-treated U87 mice and undetectable in the untreated U87 mice (maximum cycle number set to 40). This finding was replicated in GL261 mice across three different acoustic pressures. The circulating levels of eGFP mRNA were 1,500–4,800 fold higher in the FUS-treated GL261 mice than that of the untreated mice for the three acoustic pressures. This study demonstrated the feasibility of FUS-enabled brain tumor liquid biopsies in two different murine glioma models across different acoustic pressures.

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Release of Cell-free MicroRNA Tumor Biomarkers into the Blood Circulation with Pulsed Focused Ultrasound: A Noninvasive, Anatomically Localized, Molecular Liquid Biopsy

Cited by 39 publications

References 34 publications

Tumor characterization by ultrasound-release of multiple protein and microRNA biomarkers, preclinical and clinical evidence

Tumor characterization by ultrasound-release of multiple protein and microRNA biomarkers, preclinical and clinical evidence

Histotripsy: The Next Generation of High‐Intensity Focused Ultrasound for Focal Prostate Cancer Therapy

Focused Ultrasound-enabled Brain Tumor Liquid Biopsy

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