Glioblastoma

Focused Ultrasound Therapy

Focused ultrasound is a noninvasive, therapeutic which is transforming the treatment and quality of life for patients with glioblastoma. This novel technology focuses beams of ultrasonic energy precisely and accurately on targets deep in the brain without damaging surrounding normal tissue.

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 glioblastoma, 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 in the blood stream from gaining unfettered access to the brain. However, in the setting of glioblastoma, the BBB may still be intact, especially around the peripheral regions of the tumor, and preventing 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, which maximizes the detrimental effect on the targeted tissue. Clinical trials are using this technique are to provide targeted therapy to certain tumors, including glioblastomas.

Combination with Radiation
The combination of focused ultrasound and radiation has been shown to enhance the effectiveness of radiation. The joint use of these regimens is being used in patients with recurrent glioblastoma.

Ablation
Thermal ablation is one of the earliest mechanisms of action for focused ultrasound, and it is currently in use for other neurologic indications. While it was in use in some earlier clinical trials for glioblastoma, the recent efforts have shifted to the above mechanisms.

Sono-Sensitive Agents
The use of sound sensitive, ultrasound packages that can carry a variety of therapeutic agents throughout the body, and only release them when they encounter focused ultrasound is a very attractive model for treating a wide variety of diseases, including glioblastoma. This mechanism is being studied in body cancers and preclinical brain lesions currently, and it is likely to be used in clinical trials soon.

Advantages
Current treatments for glioblastoma 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 non-invasive, 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 brain tumors for focused ultrasound treatment:

Extracellular Impact of Ultrasound-induced Blood-brain Barrier Disruption  
This study of BBBD is looking at the impact of the treatment on other therapeutic and pharmacodynamic substances that may also be in the area when this is accomplished.    

An Ultrasound-Based Blood Brain Barrier Opening Clinical Trial Using Albumin Bound Paclitaxel to Treat Recurrent Glioblastoma  
This invasive procedure that is similar to focused ultrasound uses an implanted device to treat patients with recurrent glioblastoma.  

Blood-Brain Barrier Disruption (BBBD) for Liquid Biopsy in Subjects With Glioblastoma Brain Tumors  
A clinical trial for patients with Glioblastoma for liquid biopsy has also begun recruiting patients.  

The following studies concern focused ultrasound and sonodynamic therapy.  

Sonodynamic therapy in patients with recurrent glioblastoma. 
This study used oral gleolan (5 ALA) which becomes altered in the presence of focused ultrasound and becomes locally toxic to the tumor.  

A study of sonodynamic therapy for patient with high grade glioma  
A new clinical trial in the US is using sound activated drugs to treat patients with recurrent high grade glioma, including glioblastoma.  

A study of sonodynamic therapy in patients with newly diagnosed glioblastoma  
This study will use low frequency focused ultrasound to activate drugs in patients with newly diagnosed glioblastoma.  

The following studies concern tumors in pediatric patients.  
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.  

A Feasibility Safety Study of Benign Centrally-Located Intracranial Tumors in Pediatric and Young Adult Subjects  
Centrally located intracranial benign tumors that require intervention in pediatric and young adult patients. This study has completed enrollment.  

A clinical trial by Carthera is recruiting pediatric patients with recurrent malignant brain tumors in multiple locations. 

For a full list of known brain tumor clinical trials, please see here.

Regulatory Approval and Reimbursement

Focused ultrasound is not approved by any regulatory bodies worldwide as a treatment for brain tumors, 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 brain tumors. 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 to brain tumors, including the following:

• 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

Farzad Maroufi S, Sadegh Fallahi M, Parmis Maroufi S, Sheehan JP. Focused ultrasound blood-brain barrier disruption in high-grade gliomas: Scoping review of clinical studies. J Clin Neurosci. 2024 Aug 14;128:110786. doi: 10.1016/j.jocn.2024.110786. PMID: 39146579 

Bhoopathi P, Mannangatti P, Pradhan AK, Kumar A, Maji S, Lang FF, Klibanov AL, Madan E, Cavenee WK, Keoprasert T, Sun D, Bjerkvig R, Thorsen F, Gogna R, Das SK, Emdad L, Fisher PB. Noninvasive therapy of brain cancer using a unique systemic delivery methodology with a cancer terminator virus. J Cell Physiol. 2024 Aug;239(8):e31302. doi: 10.1002/jcp.31302. Epub 2024 May 22. PMID: 38775127 

McDannold N, Wen PY, Reardon DA, Fletcher SM, Golby AJ. Cavitation monitoring, treatment strategy, and acoustic simulations of focused ultrasound blood-brain barrier disruption in patients with glioblastoma. J Control Release. 2024 Jun 21;372:194-208. doi: 10.1016/j.jconrel.2024.06.036. PMID: 38897294 

Chen H, Koul D, Zhang Y, Ghobadi SN, Zhu Y, Hou Q, Chang E, Habte FG, Paulmurugan R, Khan S, Zheng Y, Graeber MB, Herschmann I, Lee KS, Wintermark M. Pulsed focused ultrasound alters the proteomic profile of the tumor microenvironment in a syngeneic mouse model of glioblastoma. J Neurooncol. 2024 Aug 24. doi: 10.1007/s11060-024-04801-4. PMID: 39180641 

Durando G, Vurro F, Saba F, Ivory AM, de Melo Baesso R, Miloro P, Spinelli AE. Combination of US hyperthermia and radiotherapy on a preclinical glioblastoma model. Sci Rep. 2024 Aug 27;14(1):19878. doi: 10.1038/s41598-024-70838-0. PMID: 39191985 

Khan ZM, Zhang J, Gannon J, Johnson BN, Verbridge SS, Vlaisavljevich E. Development of an Injectable Hydrogel for Histotripsy Ablation Toward Future Glioblastoma Therapy Applications. Ann Biomed Eng. 2024 Aug 30. doi: 10.1007/s10439-024-03601-1. PMID: 39210157 

Nwafor DC, Obiri-Yeboah D, Fazad F, Blanks W, Mut M. Focused ultrasound as a treatment modality for gliomas. Front Neurol. 2024 May 15;15:1387986. doi: 10.3389/fneur.2024.1387986. eCollection 2024. PMID: 38813245 

Chen J, Yang R, Yu H, Wu H, Wu N, Wang S, Yin X, Shi X, Wang H. Ultrasmall iron oxide nanoparticles with MRgFUS for enhanced magnetic resonance imaging of orthotopic glioblastoma. J Mater Chem B. 2024 Apr 22. doi: 10.1039/d3tb02966b. PMID: 38647018

Narsinh KH, Perez E, Haddad AF, Young JS, Savastano L, Villanueva-Meyer JE, Winkler E, de Groot J. Strategies to Improve Drug Delivery Across the Blood-Brain Barrier for Glioblastoma. Curr Neurol Neurosci Rep. 2024 May;24(5):123-139. doi: 10.1007/s11910-024-01338-x. Epub 2024

Habashy KJ, Dmello C, Chen L, Arrieta VA, Kim KS, Gould A, Youngblood MW, Bouchoux G, Bell Burdett KB, Zhang H, Canney M, Stupp R, Sonabend AM. Paclitaxel and Carboplatin in Combination with Low-Intensity Pulsed Ultrasound for Glioblastoma. Clin Cancer Res. 2024 Jan 31. doi: 10.1158/1078-0432.CCR-23-2367. PMID: 38295144 

Cai Q, Fan H, Li X, Giannotta M, Bachoo R, Qin Z. Optical Modulation of the Blood-Brain Barrier for Glioblastoma Treatment. Bio Protoc. 2024 Jan 20;14(2):e4920. doi: 10.21769/BioProtoc.4920. eCollection 2024 Jan 20. PMID: 38268976 

Chen KT, Huang CY, Pai PC, Yang WC, Tseng CK, Tsai HC, Li JC, Chuang CC, Hsu PW, Lee CC, Toh CH, Liu HL, Wei KC. Focused ultrasound combined with radiotherapy for malignant brain tumor: a preclinical and clinical study. J Neurooncol. 2023 Dec;165(3):535-545. doi: 10.1007/s11060-023-04517-x. Epub 2023 Dec 7. PMID: 38060066 

Keenlyside A, Marples T, Gao Z, Hu H, Nicely LG, Nogales J, Li H, Landgraf L, Solth A, Melzer A, Hossain-Ibrahim K, Huang Z, Banerjee S, Joseph J. Development and optimisation of in vitro sonodynamic therapy for glioblastoma. Sci Rep. 2023 Nov 18;13(1):20215. doi: 10.1038/s41598-023-47562-2. PMID: 37980454 

He C, Wu Z, Zhuang M, Li X, Xue S, Xu S, Xu J, Wu Z, Lu M. Focused ultrasound-mediated blood-brain barrier opening combined with magnetic targeting cytomembrane based biomimetic microbubbles for glioblastoma therapy. J Nanobiotechnology. 2023 Aug 26;21(1):297. doi: 10.1186/s12951-023-02074-z. PMID: 37626360 

Sonabend AM, Gould A, Amidei C, Ward R, Schmidt KA, Zhang DY, Gomez C, Bebawy JF, Liu BP, Bouchoux G, Desseaux C, Helenowski IB, Lukas RV, Dixit K, Kumthekar P, Arrieta VA, Lesniak MS, Carpentier A, Zhang H, Muzzio M, Canney M, Stupp R. Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial. Lancet Oncol. 2023 May;24(5):509-522. doi: 10.1016/S1470-2045(23)00112-2. PMID: 37142373 

Bonosi L, Marino S, Benigno UE, Musso S, Buscemi F, Giardina K, Gerardi R, Brunasso L, Costanzo R, Iacopino DG, Maugeri R. Sonodynamic therapy and magnetic resonance-guided focused ultrasound: new therapeutic strategy in glioblastoma. J Neurooncol. 2023 May;163(1):219-238. doi: 10.1007/s11060-023-04333-3. Epub 2023 May 14. PMID: 37179515 

Sun T, Krishnan V, Pan DC, Filippov SK, Ravid S, Sarode A, Kim J, Zhang Y, Power C, Aday S, Guo J, Karp JM, McDannold NJ, Mitragotri SS. Ultrasound-mediated delivery of flexibility-tunable polymer drug conjugates for treating glioblastoma. Bioeng Transl Med. 2022 Nov 19;8(2):e10408. doi: 10.1002/btm2.10408. eCollection 2023 Mar.

Zhang Y, Wang J, Ghobadi SN, Zhou H, Huang A, Gerosa M, Hou Q, Keunen O, Golebiewska A, Habte FG, Grant GA, Paulmurugan R, Lee KS, Wintermark M. Molecular Identity Changes of Tumor-Associated Macrophages and Microglia After Magnetic Resonance Imaging-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Mouse Glioblastoma Model. Ultrasound Med Biol. 2023 Jan 28:S0301-5629(22)00666-4. doi: 10.1016/j.ultrasmedbio.2022.12.006.

Porret E, Kereselidze D, Dauba A, Schweitzer-Chaput A, Jegot B, Selingue E, Tournier N, Larrat B, Novell A, Truillet C. Refining the delivery and therapeutic efficacy of cetuximab using focused ultrasound in a mouse model of glioblastoma: an 89Zr-cetuximab immunoPET study. Eur J Pharm Biopharm. 2022 Dec 15:S0939-6411(22)00300-9. doi: 10.1016/j.ejpb.2022.12.006.

Wang J, Li Z, Pan M, Fiaz M, Hao Y, Yan Y, Sun L, Yan F. Ultrasound-mediated blood-brain barrier opening: An effective drug delivery system for theranostics of brain diseases. Adv Drug Deliv Rev. 2022 Nov;190:114539. doi: 10.1016/j.addr.2022.114539. Epub 2022 Sep 15.

Lee H, Guo Y, Ross JL, Schoen S Jr, Degertekin FL, Arvanitis C. Spatially targeted brain cancer immunotherapy with closed-loop controlled focused ultrasound and immune checkpoint blockade. Sci Adv. 2022 Nov 16;8(46):eadd2288. doi: 10.1126/sciadv.add2288. Epub 2022 Nov 18.

Hersh AM, Bhimreddy M, Weber-Levine C, Jiang K, Alomari S, Theodore N, Manbachi A, Tyler BM. Applications of Focused Ultrasound for the Treatment of Glioblastoma: A New Frontier. Cancers (Basel). 2022 Oct 8;14(19):4920. doi: 10.3390/cancers14194920.

Bastiancich C, Fernandez S, Correard F, Novell A, Larrat B, Guillet B, Estève MA. Molecular Imaging of Ultrasound-Mediated Blood-Brain Barrier Disruption in a Mouse Orthotopic Glioblastoma Model. Pharmaceutics. 2022 Oct 19;14(10):2227. doi: 10.3390/pharmaceutics14102227.

Pandey N, Anastasiadis P, Carney CP, Kanvinde PP, Woodworth GF, Winkles JA, Kim AJ. Nanotherapeutic treatment of the invasive glioblastoma tumor microenvironment. Adv Drug Deliv Rev. 2022 Sep;188:114415. doi: 10.1016/j.addr.2022.114415. Epub 2022 Jul 3.

Josowitz AD, Bindra RS, Saltzman WM. Polymer Nanocarriers for Targeted Local Delivery of Agents in Treating Brain Tumors. Nanotechnology. 2022 Sep 30. doi: 10.1088/1361-6528/ac9683.

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