Diffuse Intrinsic Pontine Glioma (DIPG)

This condition is also known as Diffuse Midline Glioma (DMG)

Focused Ultrasound Therapy

Focused ultrasound is a noninvasive therapeutic technology that is transforming the treatment and quality of life for patients with Diffuse Midline Glioma (DMG), which is the newer name for Diffuse Intrinsic Pontine Glioma (DIPG), a term which is still commonly used. This novel technology focuses beams of ultrasonic energy precisely and accurately on targets in the brain without damaging surrounding normal tissue, and it is currently in clinical trials for patients with DIPG/DMG.

How it Works
Where the beams converge, the ultrasound produces a variety of therapeutic effects enabling treatment without incisions or radiation. Several different approaches are currently in consideration for this disease, and these will be briefly discussed.

Blood-Brain Barrier (BBB) Disruption
The BBB is normally a protective barrier for the brain, preventing adverse agents that may be present in the blood stream gaining unfettered access to the brain. However, in the setting of DIPG/DMG, the BBB may still be intact, and can prevent therapeutic agents (like chemotherapy) from accessing this area in sufficient quantities for maximal effect. The temporary disruption of the BBB in the targeted area enables enhanced penetration by the therapeutic agent, and following the treatment, the BBB will re-form, typically in about a day.

Sonodynamic Therapy (SDT)
Certain agents that were originally used as visual dyes to help surgeons differentiate between tumor and normal tissue, have been found to be altered after treatment by focused ultrasound, resulting in materials that are toxic to the tumor in the local area. These agents are also accumulated in tumor cells, including DIPG/DMG, which maximizes the detrimental effect on the targeted tissue. Clinical trials using this technique are providing targeted therapy to certain tumors, including DIPG/DMG.

Combination with Radiation
The combination of focused ultrasound with radiation has been shown to enhance the effectiveness of radiation. The coupling of these is being used in clinical trials for recurrent glioblastoma, and this may be an area for DIPG/DMG in the future.

Advantages
Current treatments for DIPG/DMG include surgery, radiation therapy, and chemotherapy, all of which have limitations and side effects.

Focused ultrasound, used alone or in combination with conventional therapies, has the potential for several advantages.

• Focused ultrasound is noninvasive, so it does not carry added concerns like surgical wound healing or infection.
• Focused ultrasound can reach the desired target without damaging surrounding tissue.
• Focused ultrasound does not include the use of ionizing radiation
• Focused ultrasound enables enhanced chemotherapy dose for the target, with less impact to the rest of the patient.
• It can be repeated, if necessary.

Clinical Trials

The following clinical trials are recruiting patients with DIPG/DMG for focused ultrasound treatment:

FUS Etoposide for DMG – A Feasibility Study 
This clinical trial is using focused ultrasound to temporarily open the blood brain barrier to enhance absorption of the chemotherapy agent etoposide.

Phase 1/2 Study of Sonodynamic therapy to treat Type 2 Patients with DIPG
A clinical trial is using sonodynamic therapy to treat pediatric patients who are five years and older with DIPG (diffuse intrinsic pontine glioma).

Blood Brain Barrier (BBB) Disruption Using Exablate Focused Ultrasound With Doxorubicin for Treatment of Pediatric DIPG
A clinical trial using doxorubicin to treat DIPG has begun in the US.

Blood Brain Barrier (BBB) Disruption Using Exablate Focused Ultrasound With Doxorubicin for Treatment of Pediatric DIPG
A clinical trial using doxorubicin to treat DIPG has begun in Canada.

Regulatory Approval and Reimbursement

Focused ultrasound is not approved by any regulatory bodies worldwide as a treatment for DIPG/DMG, nor is the treatment reimbursed by medical insurance providers.

Preclinical Laboratory Studies

Preclinical studies are underway to investigate the use of various mechanisms of focused ultrasound in the treatment of a wide variety of brain tumors, including DIPG/DMG. Examples of these studies include:

• Focused ultrasound to temporarily disrupt the BBB and deliver a variety of chemotherapy or immunotherapy drugs, including the dosing and timing (e.g. frequency) of drug administration.
• Focused ultrasound to induce an immune response, including a multi-site study investigating the type of immune response elicited by different “modes” of energy delivery.
• Focused ultrasound to enable targeted delivery and/or activation of drugs via carrier vehicles (e.g. microbubbles, nanoparticles, liposomes) to enable delivery of high concentrations in the tumor with minimal systemic side effects.
• Non-thermal mechanical destruction of tumor using a type of focused ultrasound called histotripsy.

Additional Resources

There are many government bodies and patient groups dedicated specifically to DIPG/DMG and also for brain tumors in general. Some examples are included below.

DIPG/DMS specific

• The DIPG/DMG Resource Network
• DIPG-ACCO American Childhood Cancer Organization
• DIPG Advocacy Group

Brain Tumor

• Medline Plus: A service of the U.S. National Library of Medicine and NIH
• National Cancer Institute’s Brain Tumor Page
• American Brain Tumor Association
• National Brain Tumor Society
• Brain Tumor Research

Notable Papers

‘t Hart E, Bianco J, Bruin MAC, Derieppe M, Besse HC, Berkhout K, Chin Joe Kie LA, Su Y, Hoving EW, Huitema ADR, Ries MG, van Vuurden DG. Radiosensitisation by olaparib through focused ultrasound delivery in a diffuse midline glioma model. J Control Release. 2023 Apr 5;357:287-298. doi: 10.1016/j.jconrel.2023.03.058.

Syed HR, Kilburn L, Fonseca A, Nazarian J, Oluigbo C, Myseros JS, Packer RJ, Keating RF. First-in-human sonodynamic therapy with ALA for pediatric diffuse intrinsic pontine glioma: a phase 1/2 study using low-intensity focused ultrasound : Technical communication. J Neurooncol. 2023 Apr 12. doi: 10.1007/s11060-023-04269-8.

Parekh K, LeBlang S, Nazarian J, Mueller S, Zacharoulis S, Hynynen K, Powlovich L. Past, present and future of Focused Ultrasound as an adjunct or complement to DIPG/DMG therapy: A consensus of the 2021 FUSF DIPG meeting. Neoplasia. 2023 Jan 27;37:100876. doi: 10.1016/j.neo.2023.100876. Online ahead of print.

Dalle Ore C, Coleman-Abadi C, Gupta N, Mueller S. Advances and Clinical Trials Update in the Treatment of Diffuse Intrinsic Pontine Gliomas. Pediatr Neurosurg. 2023 Jan 13. doi: 10.1159/000529099.  

Power EA, Rechberger JS, Gupta S, Schwartz JD, Daniels DJ, Khatua S. Drug delivery across the blood-brain barrier for the treatment of pediatric brain tumors – An update. Adv Drug Deliv Rev. 2022 Jun;185:114303. doi: 10.1016/j.addr.2022.114303. Epub 2022 Apr 21.

Tierney TS, Alavian KN, Altman N, Bhatia S, Duchowny M, Hyslop A, Jayakar P, Resnick T, Wang S, Miller I, Ragheb J. Initial experience with magnetic resonance-guided focused ultrasound stereotactic surgery for central brain lesions in young adults. J Neurosurg. 2022 Jan 14:1-8. doi: 10.3171/2021.10.JNS21416.

Batts AJ, Ji R, Kline-Schoder AR, Noel RL, Konofagou EE. Transcranial Theranostic Ultrasound for Pre-Planning and Blood-Brain Barrier Opening: A Feasibility Study Using an Imaging Phased Array In Vitro and In Vivo. IEEE Trans Biomed Eng. 2021 Oct 19;PP. doi: 10.1109/TBME.2021.3120919.

Lu N, Gupta D, Daou BJ, Fox A, Choi D, Sukovich JR, Hall TL, Camelo-Piragua S, Chaudhary N, Snell J, Pandey AS, Noll DC, Xu Z. Transcranial Magnetic Resonance-Guided Histotripsy for Brain Surgery: Pre-clinical Investigation. Ultrasound Med Biol. 2021 Oct 4:S0301-5629(21)00404-X. doi: 10.1016/j.ultrasmedbio.2021.09.008.

Liu S , Zhang W , Chen Q , Hou J , Wang J , Zhong Y , Wang X , Jiang W , Ran H , Guo D. Multifunctional nanozyme for multimodal imaging-guided enhanced sonodynamic therapy by regulating the tumor microenvironment. Nanoscale. 2021 Sep 7;13(33):14049-14066. doi: 10.1039/d1nr01449h. Epub 2021 Jul 23.

Zhang X, Ye D, Yang L, Yue Y, Sultan D, Pacia CP, Pang H, Detering L, Heo GS, Luehmann H, Choksi A, Sethi A, Limbrick DD, Becher OJ, Tai YC, Rubin JB, Chen H, Liu Y. Magnetic Resonance Imaging-Guided Focused Ultrasound-Based Delivery of Radiolabeled Copper Nanoclusters to Diffuse Intrinsic Pontine Glioma. ACS Appl Nano Mater. 2020 Nov 25;3(11):11129-11134. doi: 10.1021/acsanm.0c02297. Epub 2020 Oct 29.

Bunevicius A, Pikis S, Padilla F, Prada F, Sheehan J. Sonodynamic therapy for gliomas. J Neurooncol. 2021 Jul 12. doi: 10.1007/s11060-021-03807-6.

Raspagliesi L, D’Ammando A, Gionso M, Sheybani ND, Lopes MB, Moore D, Allen S, Gatesman J, Porto E, Timbie K, Franzini A, Di Meco F, Sheehan J, Xu Z, Prada F. Intracranial Sonodynamic Therapy With 5-Aminolevulinic Acid and Sodium Fluorescein: Safety Study in a Porcine Model. Front Oncol. 2021 Jun 21;11:679989. doi: 10.3389/fonc.2021.679989. eCollection 2021.

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