A perennial challenge in cancer treatment is figuring out how to kill tumor cells while leaving healthy cells unharmed. Two years ago, our Curious Dr. George asked Stuart L. Marcus, MD, PhD, founder and Chief Science Officer at SonALAsense, how his company’s light-activated drug treatment addresses this challenge. Here, he checks in with Dr. Marcus on the latest developments for this promising approach.
Curious Dr. George: Your flagship treatment employs sonodynamic therapy (SDT), in which focused ultrasound is used to generate a light that activates a metabolite of aminolevulinic acid (ALA) concentrated selectively in cancer cells. This approach results in the oxidative destruction of those cancer cells but not other cells. How does that work? And what can you tell us about how effective it is for cancer patients?
Stuart L. Marcus, MD, PhD: To answer how SDT works, we have to first understand that SDT is a new, noninvasive form of a light-activated drug therapy called ALA photodynamic therapy (PDT). ALA PDT targets the heme pathway selectively in cancers. When provided with excess ALA, the fluorescent photosensitizer protoporphyrin IX (PpIX) accumulates primarily in cancer tissue to such a specific extent that the U.S. Food and Drug Administration (FDA) has approved ALA-induced fluorescence in a number of different cancer settings. For instance, urologists use it to help identify bladder cancers through blue light cystoscopy. Neurosurgeons also use it every day as a visual aid to resect high-grade brain cancers, such as glioblastoma multiforme (GBM), employing blue light resection and fluorescence-detecting surgical microscopes.
When PpIX is exposed to the high energies of blue light, energy is transferred from PpIX to molecular oxygen (the photodynamic process), making it highly reactive. In 1999, the FDA approved a topical ALA PDT blue light system, which I and my team at DUSA Pharmaceuticals created for treatment of the precancerous skin condition actinic keratosis. That system, now marketed by Sun Pharmaceutical Industries, has treated over 4 million people to date. ALA PDT has also been successfully used in investigational clinical studies to treat recurrent GBM (rGBM) using the ingested dye Gleolan as the source of ALA and by inserting fiber optics within the tumor which deliver laser light. Although I considered further developing PDT for rGBM, this system is so invasive and complex that, in my opinion, commercialization is moot as the treatment is very difficult to standardize.
Instead, with ALA SDT, we use MR-guided focused ultrasound to safely create light in tissue through a process called sonoluminescence. In preclinical studies, we and others have shown that this approach can effectively and selectively kill gliomas in animal models through the PDT process and can result in complete clearing of the cancers, with 100% of the animals surviving. In a first-in-man energy dose-ranging study at the Ivy Brain Tumor Center, each of 10 rGBM patients received our intravenous form of ALA, which is called SONALA-001, and we applied SDT to one-half their tumor. The patients’ tumors were surgically removed in 4 days, and oxidative changes (lipoperoxide liberation) and apoptosis were compared in the treated and untreated halves of each tumor. We found that ALA SDT selectively caused PDT oxidative damage to the treated tumor half.
We have now treated 8 rGBM patients in a therapeutic phase 2 dose-ranging clinical trial. We have also treated 15 children with the deadly brainstem cancer diffuse intrinsic pontine glioma (DIPG) in another phase 2 dose-ranging study, in which we treat the entire brain stem. We have seen no dose-limiting toxicities in either trial, even in patients treated monthly for 10 consecutive months, attesting to the tumor-specificity of ALA as well as the lack of cumulative toxicities.
The heme pathway is a universal pathway, and the tumor-specific PpIX accumulation response to being provided with excess ALA gives us hope that SDT will prove therapeutic for many types of tumors. In December 2024, the Advanced Research Projects Agency for Health (ARPA-H), awarded our company a grant of up to $46 million USD to extend our development of SDT to the treatment of blood cancers, resulting in devices which would use SDT to treat blood cancer cells in the blood as well as within the body.
Dr. Marcus can be reached at smarcus@sonalasense.com.
