Researchers and clinicians have made great strides against many cancers but, unfortunately, not all of them. Glioblastoma multiforme (GBM) remains incredibly deadly – the five-year survival rate is a meager 5%.  Diffuse intrinsic pontine glioma (DIPG) is an almost universally fatal pediatric brain tumor. The five-year survival is around 2%. 
GBMs are generally treated with surgery and radiation. DIPG is so thoroughly embedded in the pons that surgery is impossible. Radiation can provide some small relief, and clinicians have seen some promise in CAR-T therapy.  However, the gains are uncertain and the cost in side effects quite high.
Focused ultrasound therapies have emerged as possible solutions. One approach uses the technology to open the blood brain barrier, allowing chemotherapy to penetrate the brain. Another uses focused ultrasound to improve radiation therapy. 
The most clinically advanced focused ultrasound approach is called sonodynamic therapy (known as SDT), which combines a tumor sensitizing agent and MRI-guided focused ultrasound (MRgFUS). SDT has received Orphan Drug Designation from the U.S. Food & Drug Administration (FDA) and is now in phase 1/2 studies for both GBM and DIPG; early results have been promising. This therapy could offer new hope for patients with deadly brain tumors.
The Evolution of sonodynamic therapy
SDT has its roots in photodynamic therapy. Thirty years ago, researchers showed that adding a precursor of heme called aminolevulinic acid (ALA) disrupts tumor cells’ heme metabolism. Heme is a key component in hemoglobin and other molecules. ALA has virtually no impact on healthy cells.
Hungry tumor cells feast on ALA but cannot properly metabolize it. Too much of the compound gridlocks heme production at protoporphyrin, the direct heme precursor, which accumulates in tumor cells. When hit with certain light wavelengths, protoporphyrin fluoresces and can also damage tumor cells by producing reactive oxygen species (ROS). This discovery led to photodynamic treatments for some skin cancers.
Protoporphyrin’s fluorescence has also proven useful as a visual aid for brain tumor resections, highlighting cancer cells for removal. Patients are given an oral form of ALA and neurosurgeons use a blue light to fluoresce the protoporphyrin that accumulates in glioma cells.
Clinicians have also used photodynamic therapy to treat brain cancer. Interstitial photodynamic therapy places light sources in the brain to activate ALA-induced protoporphyrin and generate ROS and cell death.
Focused Ultrasound vs. Laser Light
While photodynamic therapy has shown potential to treat GBM, and possibly other brain tumors, it has yet to progress in trials. One obvious downside is that the light sources must be implanted in the brain, making these procedures inherently invasive. However, SDT uses focused ultrasound, which is applied externally to excite the accumulated protoporphyrin in tumor cells, offering opportunities to treat tumors non-invasively.
Studies in animal glioma models showed SDT could be a promising option for human tumors. The technique generated ROS and produced apoptosis together with lipoperoxidation, reduced tumor volume and extended animal survival. Equally important, normal cells in surrounding tissue were virtually unscathed. 
Preclinical research indicated SDT could be a simple and effective treatment for GBM, DIPG and other tumors. ALA is infused intravenously and MRgFUS provides the necessary energy to agitate protoporphyrin molecules, generate ROS and kill tumor cells. This procedure could be repeated as many times as necessary to hobble, or perhaps destroy, these deadly tumors.
As with any cancer therapy, resistance is always a concern. However, SDT’s mechanism of action may insulate it from this problem. By their nature, cancer cells need new food sources. ALA infusions offer low-hanging fruit, which is why tumor cells feast on this molecule, even though they cannot digest it. ALA satisfies cancers’ innate gluttony – it’s what tumor cells want.
This contrasts to targeted therapies and other treatments, which often take away mechanisms cancers need to survive, forcing them to stochastically develop alternative pathways. While it’s possible tumor cells could mutate to resist ALA, there is no evidence they ever have. Repeated surgeries using photodynamic effects to gain better margins have shown no reductions in efficacy.
SDT in the Clinic
Beginning in 2021, and still ongoing, a phase 0/1 trial, sponsored by the Ivy Brain Tumor Center, with SonALAsense as a collaborator and led by Nader Sanai, M.D., has to date treated 10 patients. The study design was unique because clinicians only treated half the tumor volume with SDT, so that. each participant was their own control.
Four days after treatment, the tumors were removed and analyzed, and the results were quite encouraging. SDT generated ROS and apoptosis in the treated areas and produced no brain inflammation, edema, other serious adverse effects or off-target complications.
SonALAsense is following up with a phase 1/2 trial for recurrent GBM, which completed its first cohort at Cleveland Clinic in March 2023. Preliminary data from this trial should be available by the end of 2024, but early measurements are showing high blood protoporphyrin levels, which indicate ALA is getting inside tumors. The company is also planning a similar trial for patients with primary GBM.
SonALAsense is also sponsoring a phase 1/2 DIPG trial, which is being led by oncologists at Children’s National Hospital and other sites. The trial seeks to assess SDT’s safety and tolerability, as well as determining the most appropriate ALA and focused ultrasound doses.
So far, four DIPG patients have been treated without any serious adverse effects. Preliminary results should be available this year.
Next Steps for SDT
Positive preclinical and clinical results are encouraging SonALAsense and other companies to study SDT in other cancers, including primary GBM, diffuse midline gliomas beyond DIPG, tumors that metastasize to the brain and recurrent meningiomas. This approach could also be effective in bladder and pancreatic cancers.
SDT has several traits that could make it an important treatment, either as a monotherapy or in concert with more traditional approaches. First, all the preclinical and clinical evidence gathered so far has shown that it is impressively safe. Second, it’s completely noninvasive. These two traits alone mean SDT can be used periodically to control tumors. Current clinical trials are testing the therapy monthly.
Also, SDT is mutation agnostic, which is incredibly important. It doesn’t matter which variations are driving tumor growth or generating resistance to other therapies. SDT’s mechanism of action relies on tumors eating – which is what cancers do.
If SDT advances to FDA approval, it will be one more data point in favor of Occam’s Razor – the simplest solution is generally the best. But on a larger level, SDT could meet an elevated standard for cancer care, providing responses that can be measured in years rather than months. SDT has the potential to achieve something rarely seen in cancer therapeutics – truly game- changing benefits.
 Delgado-López PD, Corrales-García EM. Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol. 2016;18(11):1062-1071.doi:10.1007/s12094-016-1497-x
 Hoffman LM, van Zanten SEMV, Colditz N, et al. HG-75: Clinical, Radiological, and Histo-Genetic Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma: A Collaborative Report From the International and SIOP-E DIPG Registries. Neuro Oncol. 2016;18(Suppl 3):iii65-iii66. doi:10.1093/neuonc/now073.71
 Antonucci L, Canciani G, Mastronuzzi A, Carai A, Del Baldo G, Del Bufalo F. CAR-T Therapy for Pediatric High-Grade Gliomas: Peculiarities, Current Investigations and Future Strategies. Front Immunol. 2022;13:867154. Published 2022 May 4. doi:10.3389/fimmu.2022.867154
 Brain tumors, glioma and metastatic. Focused Ultrasound Foundation. Accessed June 14, 2023. https://www.fusfoundation.org/diseases-and-conditions/brain-tumors-glioma-and-metastatic/.
 Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol B. 1990;6(1-2):143-148. doi:10.1016/1011-1344(90)85083-9
 ohansson A, Faber F, Kniebühler G, et al. Protoporphyrin IX fluorescence and photobleaching during interstitial photodynamic therapy of malignant gliomas for early treatment prognosis. Lasers Surg Med. 2013;45(4):225-234. doi:10.1002/lsm.22126
 Wu, S-K et al (2019) MR-Guided focused ultrasound facilitates sonodynamic therapy with 5-aminolevulinic acid in a rat glioma model. Scientific Reports 9:10465 [Article].
 Suehiro S, Ohnishi T, Yamashita D, et al. Enhancement of antitumor activity by using 5-ALA-mediated sonodynamic therapy to induce apoptosis in malignant gliomas: significance of high-intensity focused ultrasound on 5-ALA-SDT in a mouse glioma model. J Neurosurg. 2018;129(6):1416-1428. doi:10.3171/2017.6.JNS162398
 Marcus S, Sanai N. DDRE-10. Metabolic Targeting of Human Glioblastoma Using 5-Aminolevulinic Acid (Ala)-Mediated Sonodynamic Therapy: A First-In-Human Study. Neurooncol Adv. 2021;3(Suppl 1):i8. Published 2021 Mar 25. doi:10.1093/noajnl/vdab024.032
 Syed HR, Kilburn L, Fonseca A, et al. 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;162(2):449-451. doi:10.1007/s11060-023-04269-8
How to Cite:
Ely Benaim, MD 1
Sonodynamic Therapy: An Emerging Treatment for Deadly Brain Tumors – Onco Zine – The International Oncology Network, July 25, 2023.