Other focused ultrasound mechanisms of action, such as sonodynamic therapy (SDT), radiation sensitization, and histotripsy have been investigated in preclinical models and are emerging in clinical trials.
Francesco Prada, MD, discussed “Sonodynamic Therapy: Concept, Mechanisms, and Application to Brain Cancer” in his prerecorded presentation (see Resources section below). Sonodynamic therapy involves activating a sonosensitizing agent (e.g., 5-ALA, fluorescein) with ultrasound, which results in the creation of reactive oxygen species leading to cell death. Sonosensitizers are chemical compounds that selectively accumulate in tumor cells, such as glioblastomas, and are currently used to guide surgical resection because they are also activated by light, which allows for improved intraoperative visualization of the tumor . Panel moderator Jason Sheehan, MD, PhD, and panelists Kullervo Hynynen, PhD, Hao-li Liu, PhD, Stuart Marcus, MD, PhD, and Francesco Prada, MD, all agreed that preclinical data support SDT as a potential treatment for GBM. Although the exact mechanism by which focused ultrasound activates 5-aminolevulinic acid (5-ALA) is not definitively understood, ablation of GBM tumor models due to apoptosis (Fig. 2C) has been achieved in preclinical studies, as evidenced by MRI and histologic evaluation [26,27,28]. Various sonosensitizers, such as 5-ALA and fluorescein, preferentially accumulate in tumoral tissue. Based on the in vivo study on large animals, there is no damage identified to the normal brain with the maximum 5-ALA dose of 100 mg/kg body weight and fluorescein dose of 20 mg/kg body weight, respectively. Intravenous 5-ALA formulation may prove safer than the oral route, because it bypasses the stomach and liver, preventing side effects (e.g., nausea, vomiting) and diminishing changes in liver function tests. In addition, the intravenous formulation may allow for more efficient delivery of 5-ALA to the tumor. There is a current clinical trial (NCT 04559685) using intravenous 5-ALA with focused ultrasound for SDT of GBM in the United States and another study (NCT 04845919) that is using oral 5-ALA in Italy (Table 2).
A prerecorded lecture by Frederic Padilla, PhD, the “Role of Focused Ultrasound for Radiosensitization of GBM,” (see Resources section below) provided an overview of the proposed mechanisms of action for how focused ultrasound causes radiosensitization of tissues. Because resistance to radiation therapy results from tumor hypoxia , increasing blood flow and oxygenation could increase radiation sensitization. Various modes of focused ultrasound, such as mild hyperthermia, can increase oxygenation and perfusion [30, 31], and nonthermal effects from focused ultrasound and microbubbles combined to open the BBB have been reported to also improve oxygenation and recruit immune cells (see Chia-Jung Lin brain tumor oral presentation and Hao-Li Liu brain tumor panel at the 2020 Focused Ultrasound International Symposium) . Focused ultrasound and microbubbles can also cause vascular shut down, leading to complete anoxia and contributing to tumor cell death downstream (Fig. 2D) [33, 34]. Greg Czarnota, MD, PhD, moderated a discussion with panelists Hao-Li Liu, PhD, and Frederic Padilla, PhD. The first-in-human clinical trial using the NaviFUS focused ultrasound system for radiosensitization of GBM (NCT 04988750) is now recruiting in Taiwan.
Zhen Xu, PhD, moderated a discussion on histotripsy as a form of mechanical focused ultrasound ablation. Panelists Tatiana Khoklova, PhD, Joan Vidal-Jove, MD, PhD, and Eli Vlaisavljevich, PhD, provided prerecorded videos on histotripsy for brain applications (see Resources section below). Histotripsy uses focused ultrasound to mechanically destroy tissue, similar to lithotripsy, and can target brain tissue and tumors in a more well-defined region and faster than focused ultrasound thermal ablation with the added benefit of avoiding skull heating. In animal models, some swelling and bleeding have been noted following intracranial histotripsy; therefore, beam parameters (e.g., frequency, number of sonications, treatment time) need to be optimized to avoid complications . Early preclinical results suggest that histotripsy may elicit an immune response. For example, mouse studies in GBM models treated with focused ultrasound released tumor antigens and recruited and activated immune cells, changing the tumor microenvironment from cold to hot . To date, there are no clinical trials with histotripsy for brain tumors.