A groundbreaking, proof-of-concept technique that will make taking a biopsy of a brain tumor, normally a complicated and invasive surgical process, as easy as a simple blood test is being developed by a team of researchers at Washington University in St. Louis.

It allows biomarkers from a brain tumor to pass through the tough blood-brain barrier into a patient’s blood using noninvasive focused ultrasound and some tiny bubbles, potentially eliminating the need for a surgical biopsy.

Hong Chen, a biomedical engineer who co-led the team, said that although researchers have already learned how to get a drug through the blood-brain barrier into the brain via the bloodstream, no one — until now — has found a way to release tumor-specific biomarkers — in this case, messenger RNA (mRNA) — from the brain into the blood.

Blood-based Liquid Biopsies

The blood test would reveal the amount of mRNA in the blood, which gives physicians specific information about the tumor that can help with diagnosis and treatment options.

“I see a clear path for the clinical translation of this technique. Blood-based liquid biopsies have been used in other cancers, but not in the brain. Our proposed technique may make it possible to perform a blood test for brain cancer patients,"

said Chen, an expert in ultrasound technology.

Chen, a biomedical engineer, and Eric C. Leuthardt, MD, a neurosurgeon, along with researchers from Washington University in St. Louis schools of Engineering and of Medicine, tested their theory in a mouse model using two different types of the deadly glioblastoma brain tumor.

Focused Ultrasound

They targeted the tumor using focused ultrasound, a technique that uses ultrasonic energy to target tissue deep in the body without incisions or radiation. Similar to a magnifying glass that can focus sunlight to a tiny point, focused ultrasound concentrates ultrasound energy to a tiny point deep into the brain.

Once they had the target — in this case, the brain tumor — researchers then injected microbubbles that travel through the blood similar to red blood cells.

When the microbubbles reached the target, they popped, causing tiny ruptures of the blood-brain barrier that allows the biomarkers from the brain tumor to pass through the barrier and release into the bloodstream. A blood sample can determine the biomarkers in the tumor.

[caption id=“attachment_95364” align=“aligncenter” width=“680”]Experimental method Experimental method.
(a) Schematic illustration of the FUS experiment setup for the treatment of U87 tumor-bearing mice.
(b) Bioluminescence image of the orthotopic mouse model with the green fluorescence image of the mouse brain shown on the right.
(c) Schematic illustration of the MRgFUS system for the treatment of GL261 tumor-bearing mice.
(d) Representative contrast-enhanced MR images acquired before and after FUS treatment. The enhanced accumulation of the MR contrast agents in the tumor region verified accurate tumor targeting by the FUS.
(e) Diagram of FUS pulses.
(f) Illustration of the experimental timeline.
Credit Zhu L, et al. CC-BY[/caption]

This technique could lead to personalized medicine.

“In many ways this has been a holy grail for brain tumor therapy. Having the ability to monitor the changing molecular events of the tumor in an ongoing way allows us to not only better diagnose a tumor in the brain, but to follow its response to different types of treatment,"

Leuthardt said.

“This noninvasive focused ultrasound-enabled liquid biopsy technique can be useful for long-term monitoring of brain cancer treatment response, where repeated surgical tissue biopsies may not be feasible. Meanwhile, variations within tumors pose a significant challenge to cancer biomarker research. Focused ultrasound can precisely target different locations of the tumor, thereby causing biomarkers to be released in a spatially-localized manner and allow us to better understand the spatial variations of the tumor and develop better treatment,"

Chen added.

The team continues to work to refine the process. The future will require integration with advanced genomic sequencing and bioinformatics to enable even more refined diagnostics.

Lifei Zhu, Galen Cheng, Dezhuang Ye, Arash Nazeri, Yimei Yue, Weijun Liu, Xiaowei Wang, Gavin P. Dunn, Allegra A. Petti, Eric C. Leuthardt & Hong Chen Focused Ultrasound-enabled Brain Tumor Liquid Biopsy Scientific Reports volume 8, Article number: 6553 (2018) doi:10.1038/s41598-018-24516-7

Top Image: brain tumor in a mouse that has been treated with green fluorescent protein-transduced glioblastoma cells. Credit: Washington University in St. Louis

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