Can Focused Ultrasound Overcome the Failure of Chemotherapy in Treating Pediatric Diffuse Intrinsic Pontine Glioma Due to a Blood-Brain Barrier Obstacle?

Abstract

Background: The blood-brain barrier (BBB) plays an important role in regulating homeostasis of the central nervous system (CNS), and it is an obstacle for molecules with a molecular weight higher than 500 Da seeking to reach it, making many drugs ineffective simply because they cannot be delivered to where they are needed. As a result, crossing the BBB remains the rate-limiting factor in brain drug delivery during the treatment of brain diseases, specifically tumors such as diffuse intrinsic pontine glioma (DIPG), a highly aggressive pediatric tumor with onset in the pons Varolii, the middle portion of the three contiguous parts of the brainstem, located above the medulla and below the midbrain. Methods: Currently, radiotherapy (RT) relieves DIPG symptoms but chemotherapy drugs do not lead to significant results as they do not easily cross the BBB. Focused ultrasound (FUS) and microbubbles (MBs) can temporarily open the BBB, facilitating radiotherapy and the entry of drugs into the CNS. A patient-derived xenograft DIPG model exposed to high-intensity focalized ultrasound (HIFU) or low-intensity focalized ultrasound (LIFU) combined with MBs was treated with doxorubicin, panobinostat, olaparib, ONC201 (Dordaviprone^®) and anti-PD1. Panobinostat has also been used in children with diffuse midline glioma, a broad class of brain tumors to which DIPG belongs. Results: Preliminary studies were performed using FUS to temporarily open the BBB and allow a milder use of radiotherapy and facilitate the passage of drugs through the BBB. The data collected show that after opening the BBB with FUS and MBs, drug delivery to the CNS significantly improved. Conclusions: FUS associated with MBs appears safe and feasible and represents a new strategy to increase the uptake of drugs in the CNS and therefore enhance their effectiveness. This review reports pre-clinical and clinical studies performed to demonstrate the usefulness of FUS in patients with DIPG treated with some chemotherapy. The papers reviewed were published in PubMed until the end of 2024 and were found using a combination of the following keywords: diffuse intrinsic pontine glioma (DIPG), DIPG H3K27-altered, blood-brain barrier and BBB, focused ultrasound (FUS) and radiotherapy (RT).

Keywords: DMG H3K27-altered; blood–brain barrier (BBB); chemotherapy; diffuse intrinsic pontine glioma (DIPG); focused ultrasound (FUS); radiotherapy (RT).

Figure 1

DIPG localization in the brain (created with Biorender.com).

Figure 2

Sonoporation of the plasma membrane, disruption of the tight junctions, and opening of the BBB by FUS (created with Biorender.com).

Figure 3

Chemical structures of doxorubicin, panobinostat, ONC201, and some PARP inhibitors (olaparib, niraparib and pamiparib).

Figure 4

Simplified mechanism of misfolded protein identification by ClpX and degradation by ClpP (modified from [83]).