Brain Tumors, Glioma and Metastatic

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Focused Ultrasound Therapy

Focused ultrasound is a noninvasive, therapeutic technology with the potential to improve the quality of life and decrease the cost of care for patients with brain tumors. 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. These include temporary opening of the blood-brain barrier, designed to improve levels in the brain of therapeutic agents; thermal ablation; activation of sono-sensitive agents at the target; and combining with radiation therapy for a more pronounce effect. There is also a study using focused ultrasound prior to surgery to help mark the boundary of the tumor extension.

Advantages
Current treatments for brain tumors 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
  • Enhanced chemotherapy dose for the target, with less impact to the rest of the patient.
  • It can be repeated, if necessary.

Clinical Trials

Exablate Blood-Brain Barrier Disruption for Glioblastoma in Patients Undergoing Standard Chemotherapy 
A clinical trial in Milan, Italy is investigating the use of focused ultrasound to open the blood-brain barrier (BBB) and allow chemotherapeutic agents to more efficiently reach the tumors of patients with glioblastoma. 

Exablate Blood-Brain Barrier Disruption for Glioblastoma in Patients Undergoing Standard Chemotherapy 
A clinical trial at Severance Hospital, a part of Yonsei University Health System, in Seoul, Korea, is investigating the use of focused ultrasound to open the blood-brain barrier (BBB) and allow chemotherapeutic agents to more efficiently reach the tumors of patients with glioblastoma. 

Exablate Blood-Brain Barrier Disruption With Carboplatin for the Treatment of rGBM 
New clinical trials have opened in the United States, Canada, and Korea that use focused ultrasound to temporarily open the blood brain barrier (BBB) prior to carboplatin therapy for patients with recurrent glioblastoma. 

Exablate Blood Brain Barrier Disruption (BBBD) for Planned Surgery in Glioblastoma 
This clinical trial is a planned continuation of a prior study that will open blood-brain barrier prior to surgery in patients with glioblastoma. 

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. 
A study of sonodynamic therapy in patients with recurrent GBM. 
A clinical trial using 5-ALA in sonodynamic therapy for patients who have recurrent or progressive glioblastoma. 

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. 

A study of 5-ALA in patients with recurrent high grade glioma
This study will use ultrasound to activate 5-ALA in adults with recurrent high grade glioma.

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. Click here for a list of tumors treated in this study. 

A clinical trial by Carthera is recruiting pediatric patients with recurrent malignant brain tumors in France. 
 
The following studies concern treatment of tumors from the body that have metastasized to the brain. 
A clinical trial for patients with breast cancer that has metastasized to their brain is enrolling patients in Canada. The team will us focused ultrasound to open the blood-brain barrier to allow therapeutic medications to more effectively reach the tumor in their brain. This study is only open to Canadian citizens. A summary of the first four patients has been published. 

A clinical trial for patients with lung cancer that has metastasized to the brain has begun recruiting patients in the US. 
 
The following study concerns a wide variety of brain tumors.
This clinical trial is for a wide variety of brain tumors that are planned to be biopsied. This study is only open to Canadian citizens. 

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

See a list of treatment sites >
See a list of clinical trials sites >
See a list of laboratory research sites >

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:

Notable Papers

Suggested Reading: Focused Ultrasound for Glioblastoma (PDF), June 2021. 

Martinez PJ, Green AL, Borden MA. Targeting diffuse midline gliomas: The promise of focused ultrasound-mediated blood-brain barrier opening. J Control Release. 2023 Nov 30;365:412-421. doi: 10.1016/j.jconrel.2023.11.037. PMID: 38000663 

Bellur S, Khosla AA, Ozair A, Kotecha R, McDermott MW, Ahluwalia MS. Management of Brain Metastases: A Review of Novel Therapies. Semin Neurol. 2023 Nov 27. doi: 10.1055/s-0043-1776782. PMID: 38011864 

Bérard C, Truillet C, Larrat B, Dhermain F, Estève MA, Correard F, Novell A. Anticancer drug delivery by focused ultrasound-mediated blood-brain/tumor barrier disruption for glioma therapy: From benchside to bedside. Pharmacol Ther. 2023 Oct;250:108518. doi: 10.1016/j.pharmthera.2023.108518. Epub 2023 Aug 22. PMID: 37619931 

Manuel TJ, Sigona MK, Phipps MA, Kusunose J, Luo H, Yang PF, Newton AT, Gore JC, Grissom W, Chen LM, Caskey CF. Small volume blood-brain barrier opening in macaques with a 1 MHz ultrasound phased array. J Control Release. 2023 Nov;363:707-720. doi: 10.1016/j.jconrel.2023.10.015. Epub 2023 Oct 17. PMID: 37827222 

Haroon J, Aboody K, Flores L, McDonald M, Mahdavi K, Zielinski M, Jordan K, Rindner E, Surya J, Venkatraman V, Go-Stevens V, Ngai G, Lara J, Hyde C, Schafer S, Schafer M, Bystritsky A, Nardi I, Kuhn T, Ross D, Jordan S. Use of transcranial low-intensity focused ultrasound for targeted delivery of stem cell-derived exosomes to the brain. Sci Rep. 2023 Oct 18;13(1):17707. doi: 10.1038/s41598-023-44785-1. PMID: 37853206 

Li B, Lin Y, Chen G, Cai M, Zhong H, Xiao Z, Lin M, Li T, Cai Y, Shuai X, Ren J. Anchoring Microbubbles on Cerebrovascular Endothelium as a New Strategy Enabling Low-Energy Ultrasound-Assisted Delivery of Varisized Agents Across Blood-Brain Barrier. Adv Sci (Weinh). 2023 Oct 23:e2302134. doi: 10.1002/advs.202302134. PMID: 37870165 

Fadera S, Chukwu C, Stark AH, Yue Y, Xu L, Chien CY, Yuan J, Chen H. Focused Ultrasound-Mediated Delivery of Anti-Programmed Cell Death-Ligand 1 Antibody to the Brain of a Porcine Model. Pharmaceutics. 2023 Oct 17;15(10):2479. doi: 10.3390/pharmaceutics15102479. PMID: 37896238 

Gao P, Sun Y, Zhang G, Li C, Wang L. A transducer positioning method for transcranial focused ultrasound treatment of brain tumors. Front Neurosci. 2023 Oct 11;17:1277906. doi: 10.3389/fnins.2023.1277906. eCollection 2023. PMID: 37904813 

Chen YH, Moore D, Lee CC, Su YH. Focused ultrasound for brain metastases: an update on global clinical trials. J Neurooncol. 2023 Nov 1. doi: 10.1007/s11060-023-04492-3. PMID: 37910281 

Cooper I, Last D, Ravid O, Rand D, Matsree E, Omesi L, Shemesh C, Liberman M, Zach L, Furman O, Daniels D, Liraz-Zaltsman S, Mardor Y, Sharabi S. BBB opening by low pulsed electric fields, depicted by delayed-contrast MRI, enables efficient delivery of therapeutic doxorubicin doses into mice brains. Fluids Barriers CNS. 2023 Sep 22;20(1):67. doi: 10.1186/s12987-023-00468-7. PMID: 37737197 

Song G, Plumlee P, Ahn JY, Wong ST, Zhao H. Translational strategies and systems biology insights for blood-brain barrier opening and delivery in brain tumors and Alzheimer’s disease. Biomed Pharmacother. 2023 Sep 11;167:115450. doi: 10.1016/j.biopha.2023.115450. PMID: 37703663 

Yuan J, Xu L, Chien CY, Yang Y, Yue Y, Fadera S, Stark AH, Schwetye KE, Nazeri A, Desai R, Athiraman U, Chaudhuri AA, Chen H, Leuthardt EC. First-in-human prospective trial of sonobiopsy in high-grade glioma patients using neuronavigation-guided focused ultrasound. NPJ Precis Oncol. 2023 Sep 16;7(1):92. doi: 10.1038/s41698-023-00448-y. PMID: 37717084 

Mehta NH, Shah HA, Ben-Shalom N, D’Amico RS. Sonolucent cranioplasty: Is therapeutic FUS the next frontier? J Clin Neurosci. 2023 Aug;114:129-130. doi: 10.1016/j.jocn.2023.06.016. Epub 2023 Jun 28. PMID: 37390776 

Grasso G, Torregrossa F, Noto M, Bruno E, Feraco P, Buscemi F, Bartolotta TV, Gagliardo C. MR-guided focused ultrasound-induced blood-brain barrier opening for brain metastasis: a review. Neurosurg Focus. 2023 Aug;55(2):E11. doi: 10.3171/2023.5.FOCUS23227. PMID: 37527681 

Zhan Y, Song Y, Qiao W, Sun L, Wang X, Yi B, Yang X, Ji L, Su P, Zhao W, Liu Z, Ren W. Focused ultrasound combined with miR-1208-equipped exosomes inhibits malignant progression of glioma. Br J Cancer. 2023 Aug 14. doi: 10.1038/s41416-023-02393-w. PMID: 37580442 

Fan B, Goodman W, Cho RY, Sheth SA, Bouchard RR, Aazhang B. Computational modeling and minimization of unintended neuronal excitation in a LIFU stimulation. Sci Rep. 2023 Aug 17;13(1):13403. doi: 10.1038/s41598-023-40522-w. PMID: 37591991 

Mehta NH, Shah HA, D’Amico RS. Sonodynamic Therapy and Sonosensitizers for Glioma Treatment: A Systematic Qualitative Review. World Neurosurg. 2023 Jul 14:S1878-8750(23)00961-0. doi: 10.1016/j.wneu.2023.07.030. PMID: 37454909  

Mehkri Y, Pierre K, Woodford SJ, Davidson CG, Urhie O, Sriram S, Hernandez J, Hanna C, Lucke-Wold B. Surgical Management of Brain Tumors with Focused Ultrasound. Curr Oncol. 2023 May 13;30(5):4990-5002. doi: 10.3390/curroncol30050377. PMID: 37232835   

Moody CT, Durham PG, Dayton PA, Brudno Y. Loading Intracranial Drug-Eluting Reservoirs Across the Blood-Brain Barrier With Focused Ultrasound. Ultrasound Med Biol. 2023 Apr 27:S0301-5629(23)00097-2. doi: 10.1016/j.ultrasmedbio.2023.03.012.  

Park J, Kong C, Shin J, Park JY, Na YC, Han SH, Chang JW, Song SH, Chang WS. Combined Effects of Focused Ultrasound and Photodynamic Treatment for Malignant Brain Tumors Using C6 Glioma Rat Model. Yonsei Med J. 2023 Apr;64(4):233-242. doi: 10.3349/ymj.2022.0422.  

Zhang DY, Dmello C, Chen L, Arrieta VA, Gonzalez-Buendia E, Kane JR, Magnusson LP, Baran A, James CD, Horbinski C, Carpentier A, Desseaux C, Canney M, Muzzio M, Stupp R, Sonabend AM. Ultrasound-mediated Delivery of Paclitaxel for Glioma: A Comparative Study of Distribution, Toxicity, and Efficacy of Albumin-bound Versus Cremophor Formulations. Clin Cancer Res. 2020 Jan 15;26(2):477-486. doi: 10.1158/1078-0432.CCR-19-2182. Epub 2019 Dec 12.  

Josowitz AD, Bindra RS, Saltzman WM. Polymer nanocarriers for targeted local delivery of agents in treating brain tumors. Nanotechnology. 2022 Dec 2;34(7). doi: 10.1088/1361-6528/ac9683.  

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.  

Mehkri Y, Woodford S, Pierre K, Dagra A, Hernandez J, Reza Hosseini Siyanaki M, Azab M, Lucke-Wold B. Focused Delivery of Chemotherapy to Augment Surgical Management of Brain Tumors. Curr Oncol. 2022 Nov 17;29(11):8846-8861. doi: 10.3390/curroncol29110696.  

Gorick CM, Breza VR, Nowak KM, Cheng VWT, Fisher DG, Debski AC, Hoch MR, Demir ZEF, Tran NM, Schwartz MR, Sheybani ND, Price RJ. Applications of focused ultrasound-mediated blood-brain barrier opening. Adv Drug Deliv Rev. 2022 Oct 19;191:114583. doi: 10.1016/j.addr.2022.114583.  

Kofoed RH, Noseworthy K, Wu K, Sivadas S, Stanek L, Elmer B, Hynynen K, Shihabuddin LS, Aubert I. The engineered AAV2-HBKO promotes non-invasive gene delivery to large brain regions beyond ultrasound targeted sites. Mol Ther Methods Clin Dev. 2022 Sep 26;27:167-184. doi: 10.1016/j.omtm.2022.09.011. eCollection 2022 Dec 8.  

Costa M, Fernandes C, Eames M, Hananel A, Mugler JP 3rd, Huaromo J, Yang JB, Mata J. Cytoreductive Surgical Treatment of Pleural Mesothelioma in a Porcine Model Using Magnetic-Resonance-Guided Focused Ultrasound Surgery (MRgFUS) and Radiofrequency Ablation (RFA). Tomography. 2022 Sep 3;8(5):2232-2242. doi: 10.3390/tomography8050187.  

Shen Y, Hu M, Li W, Chen Y, Xu Y, Sun L, Liu D, Chen S, Gu Y, Ma Y, Chen X. Delivery of DNA octahedra enhanced by focused ultrasound with microbubbles for glioma therapy. J Control Release. 2022 Aug 18;350:158-174. doi: 10.1016/j.jconrel.2022.08.019.  

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.  

Wang F, Dong L, Liang S, Wei X, Wang Y, Chang L, Guo K, Wu H, Chang Y, Yin Y, Wang L, Shi Y, Yan F, Li N. Ultrasound-triggered drug delivery for glioma therapy through gambogic acid-loaded nanobubble-microbubble complexes. Biomed Pharmacother. 2022 Jun;150:113042. doi: 10.1016/j.biopha.2022.113042. Epub 2022 May 2.  

Zhu M, Wu P, Li Y, Zhang L, Zong Y, Wan M. Synergistic therapy for orthotopic gliomas via biomimetic nanosonosensitizer-mediated sonodynamic therapy and ferroptosis. Biomater Sci. 2022 Jun 14. doi: 10.1039/d2bm00562j.  

Dong L, Li N, Wei X, Wang Y, Chang L, Wu H, Song L, Guo K, Chang Y, Yin Y, Pan M, Shen Y, Wang F. A Gambogic Acid-Loaded Delivery System Mediated by Ultrasound-Targeted Microbubble Destruction: A Promising Therapy Method for Malignant Cerebral Glioma. Int J Nanomedicine. 2022 May 3;17:2001-2017. doi: 10.2147/IJN.S344940. eCollection 2022. PMID: 35535034  

Roberts JW, Powlovich L, Sheybani N, LeBlang S. Focused ultrasound for the treatment of glioblastoma. J Neurooncol. 2022 Mar 10. doi: 10.1007/s11060-022-03974-0. Online ahead of print. PMID: 35267132  

Brighi C, Salimova E, de Veer M, Puttick S, Egan G. Translation of focused ultrasound for blood-brain barrier opening in glioma. J Control Release. 2022 Mar 23;345:443-463. doi: 10.1016/j.jconrel.2022.03.035.  

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.  

Mathew EN, Berry BC, Yang HW, Carroll RS, Johnson MD. Delivering Therapeutics to Glioblastoma: Overcoming Biological Constraints. Int J Mol Sci. 2022 Feb 2;23(3):1711. doi: 10.3390/ijms23031711.  

Ngamcherdtrakul W, Bejan DS, Cruz-Muñoz W, Reda M, Zaidan HY, Siriwon N, Marshall S, Wang R, Nelson MA, Rehwaldt JPC, Gray JW, Hynynen K, Yantasee W. Targeted Nanoparticle for Co-delivery of HER2 siRNA and a Taxane to Mirror the Standard Treatment of HER2+ Breast Cancer: Efficacy in Breast Tumor and Brain Metastasis. Small. 2022 Jan 27:e2107550. doi: 10.1002/smll.202107550.  

Gould A, Zhang D, Arrieta VA, Stupp R, Sonabend AM. Delivering albumin-bound paclitaxel across the blood-brain barrier for gliomas. Oncotarget. 2021 Dec 7;12(25):2474-2475. doi: 10.18632/oncotarget.28018. eCollection 2021 Dec 7.  
  
Samuel N, Vetkas A, Pancholi A, Sarica C, Loh A, Germann J, Harmsen IE, Tasserie J, Milano V, Yamamoto K, Kalia SK, Kongkham PN, Lozano AM. A Network-Based Approach to Glioma Surgery: Insights from Functional Neurosurgery. Cancers (Basel). 2021 Dec 5;13(23):6127. doi: 10.3390/cancers13236127.   
  
Paun L, Moiraghi A, Jannelli G, Nouri A, DiMeco F, Pallud J, Meling TR, Momjian S, Schaller K, Prada F, Migliorini D. From Focused Ultrasound Tumor Ablation to Brain Blood Barrier Opening for High Grade Glioma: A Systematic Review. Cancers (Basel). 2021 Nov 10;13(22):5614. doi: 10.3390/cancers13225614.   
  
Schoen S Jr, Kilinc MS, Lee H, Guo Y, Degertekin FL, Woodworth GF, Arvanitis C. Towards controlled drug delivery in brain tumors with microbubble-enhanced focused ultrasound. Adv Drug Deliv Rev. 2021 Nov 18;180:114043. doi: 10.1016/j.addr.2021.114043.   

Sheybani ND, Witter AR, Garrison WJ, Miller GW, Price RJ, Bullock TNJ. Profiling of the immune landscape in murine glioblastoma following blood brain/tumor barrier disruption with MR image-guided focused ultrasound. J Neurooncol. 2021 Nov 3. doi: 10.1007/s11060-021-03887-4.   
  
Serra R, Zhao T, Huq S, Gorelick NL, Casaos J, Cecia A, Mangraviti A, Eberhart C, Bai R, Olivi A, Brem H, Jackson EM, Tyler B. Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model. PLoS One. 2021 Nov 3;16(11):e0251957. doi: 10.1371/journal.pone.0251957. eCollection 2021.  

Wei HJ, Pouliopoulos A, Yoh N, Tazhibi M, McQuillan N, Zhang X, Szalontay L, Gartrell R, Jovana P, Zhang Z, Feldstein N, Zacharoulis S, Konofagou EE, Wu CC. Focused Ultrasound-Mediated Blood-Brain Barrier Opening Enhances Panobinostat Efficacy in a Murine Diffuse Intrinsic Pontine Glioma Model. Int J Radiat Oncol Biol Phys. 2021 Nov 1;111(3S):e177. doi: 10.1016/j.ijrobp.2021.07.666.  

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.  

Meng Y, Pople CB, Budiansky D, Li D, Suppiah S, Lim-Fat MJ, Perry J, Sahgal A, Lipsman N. Current state of therapeutic focused ultrasound applications in neuro-oncology. J Neurooncol. 2021 Oct 18. doi: 10.1007/s11060-021-03861-0.  

Meng Y, Reilly R, Pezo R, Trudeau M, Sahgal A, Singnurkar A, Perry J, Myrehaug S, Pople C, Davidson B, Llinas M, Hyen C, Huang Y, Hamani C, Suppiah S, Hynynen K, and Lipsman N. MR-guided focused ultrasound enhances delivery of trastuzumab to Her2-positive brain metastases. Science Translational Medicine 13 Oct 2021 Vol 13, Issue 615 DOI: 10.1126/scitranslmed.abj4011  

Click here for additional references from PubMed. 


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