A groundbreaking mechanotherapy approach combining low-intensity focused ultrasound with TRAIL protein shows significant reduction in prostate cancer tumours through synergistic activation of cell death pathways.
Photo by Gustavo Raskosky/Rice University
A collaborative study led by researchers at Rice University and Vanderbilt University has demonstrated that combining a protein therapy called tumour necrosis factor related apoptosis-inducing ligand (TRAIL) with focused ultrasound (FUS) can significantly reduce tumour size in prostate cancer models. The research, published in the journal Advanced Science on 21 February 2025, represents the first evidence that low-intensity mechanical force combined with TRAIL can effectively treat cancers.
“There is urgent need to improve how we treat advanced and recurrent prostate cancer, which is the second-leading cause of death among men in the United States and is the most frequently diagnosed cancer in more than 100 countries,” said study lead author Michael King, the E.D. Butcher Professor of Bioengineering at Rice University. “We have now found a safe, effective and noninvasive way to enhance the antitumor effects of a specific cancer drug (TRAIL), a promising finding which we are hopeful can soon be translated for clinical care.”
The challenge with current cancer treatments
Current standard-of-care treatments for prostate cancer often come with severe adverse effects. High-intensity focused ultrasound (HIFU) therapies have gained attention for their ability to target tumour tissue specifically, but they can still cause unwanted side effects such as skin burns and urinary complications.
TRAIL protein specifically induces death in cancer cells while sparing healthy cells. However, despite promising laboratory results, clinical trials with TRAIL have shown limited success due to its very short half-life in circulation (approximately 30 minutes).
“Previously, we had found certain mechanical forces like fluid shear stress could amplify the anticancer effects of TRAIL with an influx of calcium and activation of a protein called Piezo1 that triggered cell death,” explained King. However, fluid shear stress is only present in circulatory and lymphatic systems, making it ineffective against solid tumours.
How focused ultrasound enhances TRAIL’s cancer-killing effects
The researchers discovered that low-intensity focused ultrasound (LIFU) can mechanically activate Piezo1, a mechanosensitive ion channel that enhances TRAIL’s cancer-killing abilities. This activation allows calcium to enter cancer cells, triggering the intrinsic apoptosis (cell death) pathway.
Using prostate cancer cell lines, graduate students Abigail Fabiano and Malachy Newman performed experiments to optimise the ultrasound parameters while ensuring nearby healthy cells remained unharmed. The team found that combination therapy of FUS and TRAIL was much more effective than either treatment alone.
“As the FUS pressure increased, the TRAIL-mediated apoptosis increased more notably in the PC3 cells in comparison to the LNCaP cells,” the authors state in the paper. This is significant because PC3 cells represent a more advanced metastatic state of prostate cancer than LN-CaP cells, suggesting the therapy could be effective against aggressive forms of the disease.
The researchers confirmed that the mechanism behind this enhanced effect involves Piezo1 activation by:
Demonstrating reduced effectiveness when they blocked calcium with chelating agents
Using pharmacological inhibitors of mechanosensitive ion channels
Conducting gene knockdown experiments targeting Piezo1
“These results exemplify that disruption of the mechanoactivation of Piezo1 affects the efficacy of this combination therapy to induce apoptosis,” the authors note.
Impressive results in animal models
When tested in mouse models, the combination therapy significantly reduced tumour burden compared to either FUS or TRAIL alone. The researchers administered two treatments, six days apart, and monitored tumour growth for 62 days.
On day 62 post-tumour cell inoculation, the mean volume of tumours treated with the combination therapy was 529 ± 170 mm³, significantly smaller than tumours treated with control or single treatments. Importantly, the researchers found no evidence of harmful thermal effects or damage to surrounding tissues.
“Overall, higher Piezo1 expression correlated with lower tumour burden in vivo, and decreased for the FUS condition,” the authors report. “Considering that Piezo1 is elevated in PCa, this could indicate that the mechanical effects of FUS alone can both activate and potentially downregulate expression of Piezo1 over time.”
The team also examined different time intervals between TRAIL injection and FUS exposure, finding that immediate application (0 hours) and 4-hour intervals produced the best results in reducing tumour growth.
Clinical translation potential
“This mechanotherapy offers a clinically translatable approach by utilizing widely available FUS technology, applicable to treat additional cancer types,” the authors conclude. The approach has several advantages over existing therapies:
- It uses low-intensity FUS, avoiding thermal ablation and damage associated with higher-intensity treatments
- The therapy is noninvasive and precisely targeted
- It activates cancer cell death pathways while sparing healthy cells
- The mechanical index used was well below FDA safety limits
“Development of noninvasive, safe, and effective treatment options for PCa are sorely needed, considering the risk that other therapeutic options impose on the patient’s quality of life,” the authors state in their discussion. “The mechanotherapy presented here exemplifies how FUS can target tumours and enhance the pro-apoptotic effects of soluble TRAIL.”
Future directions
The researchers suggest this approach could be combined with other cancer therapies or modified to treat different types of cancer. The technology is particularly promising because focused ultrasound equipment is already widely available in clinical settings.
“This foundational study provides crucial preclinical insights that can be used to develop a novel combination therapy for prostate cancer,” said King. “Furthermore, it opens the doors to many new avenues for using mechanotherapy in medicine and has far-reaching implications in how FUS and other mechanical therapies can be combined with small-molecule protein therapy and other drugs to effectively treat various types of cancers with fewer adverse effects in the future.”
The research team believes this mechanotherapy could be easily translated to examine success in treating other cancers, including those that are difficult to treat with conventional methods.
Reference:
Fabiano, A.R., Newman, M.W., Dombroski, J.A., et. al. (2025). Applying Ultrasound to Mechanically and Noninvasively Sensitize Prostate Tumors to TRAIL-Mediated Apoptosis. Advanced Science, 2412995. https://doi.org/10.1002/advs.202412995
