Mention glioblastoma (GBM) to anyone with some knowledge of the disease, and the mood instantly turns grim. These tumors are clinically challenging for many reasons, but it’s more than that. What they do to patients is horrific, on par with Alzheimer’s disease or ALS.

As people fight their cancer, with each surgery or radiation treatment, they gradually waste away. They lose physical and cognitive function, sometimes their personalities change, and eventually, the tumor kills them. The five-year survival rate for GBM is 5%. By contrast, the five-year survival for pancreatic cancer, another incredibly difficult tumor, is around 10%.[1][2]

GBM is so challenging because it’s difficult to get at and defies existing treatments. The blood-brain barrier excludes almost all chemo and biologic therapies. Surgeons have great difficulty with GBM tumors because they infiltrate the brain, are often difficult to visualize, and require great caution during resection. Radiation faces similar issues. At best, these therapies buy time.

To further complicate matters, these tumors are genetically and epigenetically diverse. There are no specific mutations, like EGFR or RAS, that drive these cancers. In a sense, each patient’s tumor is like a malignant snowflake, a unique entity.

Axplora

A Therapeutic Evolution
In the 1990s, researchers found aminolevulinic acid (ALA) accumulates in skin carcinoma cells. ALA is an essential component in the heme metabolic pathway, but cancer cells have trouble regulating this process: Too much ALA creates a bottleneck at the penultimate step. Instead of completing the cycle and producing heme, cancer cells get hung up producing protoporphyrin. [3]

Advertisement #3

From an oncological standpoint, protoporphyrin has some interesting properties. It fluoresces when exposed to certain wavelengths, making it useful as a visual aid to surgically resect GBMs. [4] When activated with high light energies, however, it produces reactive oxygen species (the photodynamic effect), which can be used to kill cancer cells. As a result, photodynamic therapy (PDT) was developed to treat skin basal cell carcinomas and precancerous skin lesions.[5]

Around 2012, clinical researchers showed that dosing GBM patients with ALA and exposing them to laser light carried by fiber optics inserted into the tumor (interstitial PDT) could extend survival in some patients with recurrent glioblastoma, but the procedure was invasive and complex.

Around the same time, a study found focused ultrasound, combined with ALA, can produce the same photodynamic effect in animal glioma models. Later studies supported these initial findings and found these treatments, called sonodynamic therapy, could extend the animals’ lives from 21 to 60 days, an enormous benefit and particularly promising if it could be extrapolated to human patients. [6]

Pan GBM
ALA sonodynamic therapy for GBM offers the promise of being both targeted and comprehensive. It’s targeted because it should be highly selective for fast-growing GBM tumors while barely affecting slow-growing normal cells.

It’s comprehensive because the therapy is agnostic to a tumor’s genetics or epigenetics. Regardless of the mutations driving GBM growth, these cells must still synthesize heme to carry out their energy metabolism. As a result, they will continue to drink up as much ALA as they are given. Sonodynamic therapy simply targets a basic necessity, turning the tumor’s metabolism against itself.

Will GBMs figure out how to evade this therapy, as cancers often do? It seems unlikely. Circling back to ALA fluorescence-guiding surgery, these procedures are often repeated in a constant battle to debulk patients’ tumors. However, even multiple GBM recurrences do not mitigate the fluorescence from ALA. From what we know so far, this GBM-specific quirk in the heme metabolic pathway seems quite durable. [4]

Phase 0 Results
The Ivy Brain Tumor Center in Arizona is in the process of completing a phase 0/1 study on ALA sonodynamic therapy for GBM. Traditionally, phase 0 trials determine whether a drug actually reaches its intended target. However, in this case, it’s accepted that ALA will accumulate in GBM cells and ultimately generate protoporphyrin.

Rather, this study was designed to determine whether human GBM tumors react to sonodynamic therapy like animal gliomas. Each patient serves as their own control because only half of each patient’s tumor is exposed to sonodynamic therapy. Both the sonodynamic therapy-treated half and the untreated (control) half are analyzed following surgery.

So far, the results have been quite encouraging. ALA sonodynamic therapy generated reactive oxygen species and apoptosis in the treated areas within three to four days, closely adhering to the animal model results. Equally important, patients experienced no unexpected side effects.

Researchers are still working on the appropriate doses. However, even the lowest dose regimen tested demonstrated the anticipated effects on tumors.

This is great news, but we’re not popping the champagne just yet. We will continue to rigorously test ALA sonodynamic therapy in GBM, and other brain tumors, to clarify the most appropriate doses and test for efficacy. However, all caveats accepted, we dare to dream that we can make significant headway against this horrific and intractable disease with this noninvasive, rapidly acting therapy that turns the tumor’s energy metabolism against itself.

Clinical trials
Study of Sonodynamic Therapy in Participants With Recurrent High-Grade Glioma – NCT04559685
Sonodynamic Therapy With ExAblate System in Glioblastoma Patients (Sonic ALA) – NCT04845919

Prescribing information
Aminolevulinic Acid HCL for Topical Solution, 20% (Levulan® Kerastick®; DUSA Pharmaceuticals, a Sun Pharma company)[Prescribing Information]

References
[1] Delgado-López PD, Corrales-García EM. Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol. 2016 Nov;18(11):1062-1071. doi: 10.1007/s12094-016-1497-x. Epub 2016 Mar 10. PMID: 26960561.
[2] Miller AL, Garcia PL, Yoon KJ. Developing effective combination therapy for pancreatic cancer: An overview. Pharmacol Res. 2020 May;155:104740. doi: 10.1016/j.phrs.2020.104740. Epub 2020 Mar 2. PMID: 32135247; PMCID: PMC7365261.
[3] Kennedy J et al (1990) Photodynamic therapy with endogenous protoporphyrin IX: Basic principles and present clinical experience, J Photochem. Photobiol. B: 6; 143-148
[4] Chohan, MO and Berger, M (2018) 5-Aminolevulinic acid fluorescence-guided surgery for recurrent high-grade gliomas. J Neuro-Oncology https://doi.org/10.1007/s11060-018-2956-8
[5] LEVULAN KERASTICK photodynamic therapy. Online Last Accessed on October 28, 2021
[6] 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 https://doi.org/10.1038/s41598-019-46832-2.

Byondis
Advertisement #5