Applications of Focused Ultrasound for the Treatment of Glioblastoma: A New Frontier

Abstract

Glioblastoma (GBM) is an aggressive primary astrocytoma associated with short overall survival. Treatment for GBM primarily consists of maximal safe surgical resection, radiation therapy, and chemotherapy using temozolomide. Nonetheless, recurrence and tumor progression is the norm, driven by tumor stem cell activity and a high mutational burden. Focused ultrasound (FUS) has shown promising results in preclinical and clinical trials for treatment of GBM and has received regulatory approval for the treatment of other neoplasms. Here, we review the range of applications for FUS in the treatment of GBM, which depend on parameters, including frequency, power, pulse duration, and duty cycle. Low-intensity FUS can be used to transiently open the blood–brain barrier (BBB), which restricts diffusion of most macromolecules and therapeutic agents into the brain. Under guidance from magnetic resonance imaging, the BBB can be targeted in a precise location to permit diffusion of molecules only at the vicinity of the tumor, preventing side effects to healthy tissue. BBB opening can also be used to improve detection of cell-free tumor DNA with liquid biopsies, allowing non-invasive diagnosis and identification of molecular mutations. High-intensity FUS can cause tumor ablation via a hyperthermic effect. Additionally, FUS can stimulate immunological attack of tumor cells, can activate sonosensitizers to exert cytotoxic effects on tumor tissue, and can sensitize tumors to radiation therapy. Finally, another mechanism under investigation, known as histotripsy, produces tumor ablation via acoustic cavitation rather than thermal effects.

Focused ultrasound for treatment of peripheral brain tumors

“…This thermal effect is achieved when the local temperature reaches the threshold for protein denaturation and tissue damage and subsequent lesion formation [ 18 , 51 ]. This thermoablative process further increases tumor sensitivity to radiation by damaging deoxyribonucleic acid (DNA) repair enzymes [ 2 ].…”

“…However, other types of tumors currently being investigated include astrocytomas, ependymomas, cranial nerve tumors, meningiomas, metastases, neuronal tumors, pineal tumors, and tumors in the sellar region [ 121 ]. Hersh et al [ 2 ] found the reason for optimism in using both modalities to treat GBM [ 2 ]. However, limited sample sizes and outdated technologies have obscured the data.…”

“…Over 260,000 people are diagnosed with primary malignant central nervous system (CNS) tumors annually. Malignant brain tumors are the leading cause of cancer-related death in children and the third largest cause of death in young adults [ 1 , 2 ]. Currently, brain tumors are typically treated with surgical resection and radiotherapy in addition to chemotherapy or other therapeutic molecules [ 3 – 5 ].…”

Advanced Radio Frequency Applicators for Thermal Magnetic Resonance Theranostics of Brain Tumors

“…Localized thermal therapy as a potent sensitizer of chemo-, radio- or immunotherapy of cancers has been reported to show clinical benefits [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. Technical developments and research directions of thermal therapy have followed several trajectories, including magnetic nanoparticle hyperthermia (MNH), focused ultrasound-based hyperthermia, microwave-induced hyperthermia and radio frequency (RF)-driven hyperthermia [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. With an ever-increasing clinical interest in thermal therapy, non-invasive in vivo approaches that facilitate diagnostic imaging-guided temperature therapy, along with the characterization of its subsequent effects, are imperative.…”

Sonodynamic therapy and Magnetic Resonance-guided Focused Ultrasound: new therapeutic strategy in Glioblastoma

“…Various new treatments have been proposed over the years, regarding use of CAR T cells [13], molecular agents enhancing the effect of Radiotherapy (RT) [14], up to the application of high and low intensity focus ultrasound [15].…”