Feature

Liquid biopsy technique may detect brain tumor biomarkers

Hong Chen

A team of researchers at Washington University in St. Louis is developing a way to detect brain tumor biomarkers through a blood test.

The proof-of-concept technique allows biomarkers from a brain tumor to pass through the blood-brain barrier into a patient’s blood using noninvasive focused ultrasound and microbubbles. The focused ultrasound technique could be viewed as a tool for enhancing ‘two-way trafficking’ between the brain and blood.

“Focused ultrasound opens a door between the blood circulation and the brain tissue,” Hong Chen, PhD, assistant professor in the departments of biomedical engineering and radiation oncology at Washington University in St. Louis, told HemOnc Today. “Although previous work has focused on the delivery of drugs across this door from the blood to the brain for the treatment of brain diseases, our work proposed that biomarkers can be released across the same door from the brain to the blood.”

HemOnc Today spoke with Chen about how this technique works, the efficacy it has demonstrated so far and what must be confirmed in subsequent research.

 

Question: How was this technique discovered?

Answer: For many cancers outside of the brain, important molecular characterizations of tumors could be obtained from a blood draw. However, limited progress has been made for brain tumor blood-based liquid biopsy. The major challenge is the hindrance of tumor biomarker release into the bloodstream by the blood-brain barrier. Focused ultrasound in combination with microbubbles has been shown to be a promising technique for noninvasive and localized disruption of the blood-brain barrier for the delivery of drugs in the blood circulation to the brain. Ongoing clinical trials are evaluating the feasibility and safety of focused ultrasound-induced blood-brain barrier opening among patients with glioblastoma and Alzheimer’s disease. Building on these seminal works, we propose to develop a focused ultrasound-enabled brain tumor liquid biopsy technique, which uses focused ultrasound in combination with microbubbles to enhance the release of biomarkers from brain tumors into the blood circulation for liquid biopsies.

 

Q: How does the technique work?

A: Currently, when a brain tumor is diagnosed, neurosurgeons will need to open a hole in the skull and surgically remove a piece of the tumor. The removed tissue can be used to test the genetic makeup of the tumor and assist in making decisions about how to treat it. As one can imagine, this tissue biopsy procedure is associated with potential hemorrhage and infection. Repeated tissue biopsies to assess treatment response may not be feasible.

The technique we propose is fully noninvasive. Microbubbles, which have been used in the clinic as ultrasound contrast agents for more than 20 years, are injected intravenously. Then, a focused ultrasound transducer will be placed on the head and noninvasively shoot ultrasound to the brain. Upon ultrasound exposure, these microbubbles expand, contract and pop, generating mechanical forces to surrounding blood vessels. This mechanical interaction can lead to disruption of the blood-brain barrier, allowing biomarkers to be released from the brain into the blood circulation. The procedure is just like performing a diagnostic ultrasound scan, but with a specially designed ultrasound transducer.

Q: Can you describe the efficacy observed so far?

A: We demonstrated the feasibility of using this technique for the local release of mRNA from glioblastoma tumors in mice into the bloodstream for liquid biopsies. The biomarker we used was enhanced green fluorescent protein (eGFP) mRNA, which was highly specific to the tumor models used in this study, as the tumor models were established by the direct injection of eGFP-luciferase-transduced glioblastoma cells into the mouse brain.

 

Q: What still must be confirmed in subsequent research?

A: The short-term and long-term safety of this technique needs to be confirmed. The sensitivity and specificity of this technique also need to be evaluated.

 

Q: What studies — if any — are planned to do further evaluation of this technique?

A: Optimal treatment parameters for efficient and safe biomarker release need to be defined. Feasibility and safety in large animals need to be tested to pave the way for future clinical translation.

 

Q: What are the potential implications if this approach is proven effective?

A: If this technique is proven effective, physicians can collect the blood and detect the expression level of biomarkers in the patient for brain tumor detection and guide the choice of treatment for individual patients. The application of this technique is not limited to brain tumors. It can potentially be expanded to other tumor types, as well as other brain diseases. – by Jennifer Southall

 

Reference:

Zhu L, et al. Sci Rep. 2018;doi:10.1038/s41598-018-24516-7.

For more information:

Hong Chen, PhD, can be reached at Washington University in St. Louis, Brauer Hall, Room 2004, 1 Brookings Drive, Saint Louis, MO 63130; email: hongchen@wustl.edu.

Disclosure: Chen reports no relevant financial disclosures.

Hong Chen

A team of researchers at Washington University in St. Louis is developing a way to detect brain tumor biomarkers through a blood test.

The proof-of-concept technique allows biomarkers from a brain tumor to pass through the blood-brain barrier into a patient’s blood using noninvasive focused ultrasound and microbubbles. The focused ultrasound technique could be viewed as a tool for enhancing ‘two-way trafficking’ between the brain and blood.

“Focused ultrasound opens a door between the blood circulation and the brain tissue,” Hong Chen, PhD, assistant professor in the departments of biomedical engineering and radiation oncology at Washington University in St. Louis, told HemOnc Today. “Although previous work has focused on the delivery of drugs across this door from the blood to the brain for the treatment of brain diseases, our work proposed that biomarkers can be released across the same door from the brain to the blood.”

HemOnc Today spoke with Chen about how this technique works, the efficacy it has demonstrated so far and what must be confirmed in subsequent research.

 

Question: How was this technique discovered?

Answer: For many cancers outside of the brain, important molecular characterizations of tumors could be obtained from a blood draw. However, limited progress has been made for brain tumor blood-based liquid biopsy. The major challenge is the hindrance of tumor biomarker release into the bloodstream by the blood-brain barrier. Focused ultrasound in combination with microbubbles has been shown to be a promising technique for noninvasive and localized disruption of the blood-brain barrier for the delivery of drugs in the blood circulation to the brain. Ongoing clinical trials are evaluating the feasibility and safety of focused ultrasound-induced blood-brain barrier opening among patients with glioblastoma and Alzheimer’s disease. Building on these seminal works, we propose to develop a focused ultrasound-enabled brain tumor liquid biopsy technique, which uses focused ultrasound in combination with microbubbles to enhance the release of biomarkers from brain tumors into the blood circulation for liquid biopsies.

 

Q: How does the technique work?

A: Currently, when a brain tumor is diagnosed, neurosurgeons will need to open a hole in the skull and surgically remove a piece of the tumor. The removed tissue can be used to test the genetic makeup of the tumor and assist in making decisions about how to treat it. As one can imagine, this tissue biopsy procedure is associated with potential hemorrhage and infection. Repeated tissue biopsies to assess treatment response may not be feasible.

The technique we propose is fully noninvasive. Microbubbles, which have been used in the clinic as ultrasound contrast agents for more than 20 years, are injected intravenously. Then, a focused ultrasound transducer will be placed on the head and noninvasively shoot ultrasound to the brain. Upon ultrasound exposure, these microbubbles expand, contract and pop, generating mechanical forces to surrounding blood vessels. This mechanical interaction can lead to disruption of the blood-brain barrier, allowing biomarkers to be released from the brain into the blood circulation. The procedure is just like performing a diagnostic ultrasound scan, but with a specially designed ultrasound transducer.

 

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Q: Can you describe the efficacy observed so far?

A: We demonstrated the feasibility of using this technique for the local release of mRNA from glioblastoma tumors in mice into the bloodstream for liquid biopsies. The biomarker we used was enhanced green fluorescent protein (eGFP) mRNA, which was highly specific to the tumor models used in this study, as the tumor models were established by the direct injection of eGFP-luciferase-transduced glioblastoma cells into the mouse brain.

 

Q: What still must be confirmed in subsequent research?

A: The short-term and long-term safety of this technique needs to be confirmed. The sensitivity and specificity of this technique also need to be evaluated.

 

Q: What studies — if any — are planned to do further evaluation of this technique?

A: Optimal treatment parameters for efficient and safe biomarker release need to be defined. Feasibility and safety in large animals need to be tested to pave the way for future clinical translation.

 

Q: What are the potential implications if this approach is proven effective?

A: If this technique is proven effective, physicians can collect the blood and detect the expression level of biomarkers in the patient for brain tumor detection and guide the choice of treatment for individual patients. The application of this technique is not limited to brain tumors. It can potentially be expanded to other tumor types, as well as other brain diseases. – by Jennifer Southall

 

Reference:

Zhu L, et al. Sci Rep. 2018;doi:10.1038/s41598-018-24516-7.

For more information:

Hong Chen, PhD, can be reached at Washington University in St. Louis, Brauer Hall, Room 2004, 1 Brookings Drive, Saint Louis, MO 63130; email: hongchen@wustl.edu.

Disclosure: Chen reports no relevant financial disclosures.