HOUSTON – (Feb. 21, 2025) – Combining an existing small-molecule protein therapy called tumor necrosis factor related apoptosis-inducing ligand (TRAIL) with focused ultrasound (FUS) can significantly reduce tumor size and burden in prostate cancer models, according to a new study published in Advanced Science by researchers at Rice University and Vanderbilt University .
Around the world, about 10 million people die of cancer each year. This collaborative study, led by Michael King , the E.D. Butcher Professor of Bioengineering in the George R. Brown School of Engineering and Computing at Rice, and Charles Caskey , associate professor in radiology and radiological sciences at Vanderbilt, is the first to demonstrate that low-intensity mechanical force in combination with TRAIL can treat cancers.
The study sheds new light on how low-intensity focused ultrasound and soluble TRAIL specifically destroy cancer cells within the compact environment of a primary prostate cancer lesion.
Urgency for safe, effective therapy for prostate cancer
"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 King, who is a Cancer Prevention and Research Institute of Texas Scholar. "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."
Current standard-of-care prostate cancer treatments are associated with severe adverse effects. In recent years, FUS-based therapies have been gaining attention since they can be localized specifically to tumor tissue, resulting in fewer off-target effects.
Mechanical stimuli amplify anticancer effects of TRAIL via Piezo1
TRAIL protein specifically induces the death of cancer cells without harming nearby healthy cells. However, despite promising results in lab studies, only a few cancer patients have shown improvements with intravenous administration of TRAIL in clinical trials. This is because TRAIL has a very short half-life (~30 minutes) and remains in blood circulation only briefly before it gets destroyed.
Thus, to effectively eliminate cancer cells, TRAIL therapy needs to be administered multiple times per day, which is not only inconvenient but also increases the risk of unwanted side effects.
"Previously, we had found certain mechanical forces like fluid shear stress (FSS) could amplify the anticancer effects of TRAIL with an influx of calcium and activation of a protein called Piezo1 that triggered cell death," King said.
However, FSS is not clinically applicable for solid tumors because it is only present in the circulatory and lymphatic systems and thus only effective against circulating tumor cells, which are often observed at later stages of malignancy.
"The field is still lacking a straightforward and effective clinical approach that combines the application of mechanical force with soluble TRAIL as a localized therapeutic to treat primary prostate tumors effectively before they metastasize to different locations, which prompted us to undertake this preclinical study to examine if FUS might be a good candidate to be developed into a combination therapy for prostate cancer," King said.
Low-intensity FUS acts synergistically with TRAIL to reduce prostate tumors in lab
Using prostate cancer cell lines, Abigail Fabiano and Malachy Newman — graduate students mentored by King and Caskey respectively — performed several experiments to refine and optimize several operational parameters of in vitro FUS.
Their initial goal was to ensure that the nearby healthy cells remained unharmed by the mechanical shear forces. Next, they found that combination therapy of FUS and TRAIL was much more effective in reducing the number of cancer cells and size of tumors than FUS or TRAIL alone, supporting the idea that the synergistic action of TRAIL and FUS-mediated Piezo1 activation is key to achieving maximum tumor reduction.
"This foundational study provides crucial preclinical insights that can be used to develop a novel combination therapy for prostate cancer," King said. "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."
This research was funded by a grant from the National Institutes of Health (R01CA256054, P30CA068485, S10 OD023475-01A1) and the National Science Foundation (2021314768). The content herein is solely the responsibility of the authors and does not necessarily represent the official views of the funders.
⎯ by Raji Natarajan, science writer, George R. Brown School of Engineering and Computing
