Sonodynamic Therapy With ExAblate System in Glioblastoma Patients

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Despite progress made in many cancer treatments, high-grade gliomas (HGG) remain an extraordinary challenge. Their aggressive and infiltrative nature, the limited efficacy and inherent risk of surgical resection combined with radiotherapy, and the difficulty in delivering anticancer drugs to the bra...

Despite progress made in many cancer treatments, high-grade gliomas (HGG) remain an extraordinary challenge. Their aggressive and infiltrative nature, the limited efficacy and inherent risk of surgical resection combined with radiotherapy, and the difficulty in delivering anticancer drugs to the brain, make the prognosis for patients with gliomas grim. Therefore, new and less-invasive alternatives to existing procedures are needed. Sonodynamic therapy (SDT) represents an emerging approach that offers the possibility of non-invasively eradicating solid tumors in a site-directed manner. It involves the delivery of a non-toxic chemical agent that selectively accumulates into target areas and the subsequent exposure of the targeted tissue to relatively low-intensity ultrasound. These procedures (sensitization and ultrasound exposure) are both per se harmless, but, when combined, result in activation of the chemical agent and subsequent cytotoxic events limited to the target tissue volume. SDT offers significant advantages because ultrasound energy can be tightly focused and delivered through the intact skull to deep areas of the brain, depending on the frequency. SDT is achieved by focusing low-intensity and low-frequency ultrasound, which, as opposite to high-intensity ultrasonic beams, can be focused effectively within the whole intracranial space with the currently available device (ExAblate 4000, Insightec, Haifa, Israel). This would enable to target also tumors in the peripheral area of the intracranial space. 5-ALA is a protoporhyrin IX (PpIX) precursor that selectively accumulates in HGGs because of an enhanced uptake and metabolism from tumor cells. It is used for intra-operative guidance in surgery as tumoral tissues shows an exceeding fluorescence under certain light conditions due to PpIX accumulation, as compared to the normal surrounding parenchyma. It is therefore a good candidate for SDT. 5-ALA can exert sonodynamic effects against HGGs, as it has been shown in several pre-clinical studies. Unpublished pre-clinical data on a safety experiment conducted at the University of Virginia showed that SDT with 5-ALA was not exerting a toxic effect to the normal brain. The idea of the present study is to investigate the antitumor effects of SDT in patients affected by HGGs attained with low-frequency focused ultrasound. Focused ultrasound under MRI-guidance can be safely delivered through an intact human skull to perform SDT in combination with 5-ALA with a low risk of transient adverse effects, as evaluated during follow-up visits, post-procedural serial MRI and histology.

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