Establishing a New Therapeutic Platform
UVA's Move to the Forefront of Focused Ultrasound
Novelist John Grisham and UVA Professor Richard Price have at least one thing in common: They both believe that focused ultrasound can dramatically improve outcomes for patients with cancer and other diseases. A board member of the Charlottesville-based Focused Ultrasound Foundation, Grisham has done what novelists do: he has written a book, The Tumor, a thriller that dramatizes and publicizes its potential.
Price, a biomedical engineer and expert on focused ultrasound drug and gene delivery, has advanced the cause in his own way: He serves as research director of the UVA Focused Ultrasound Center.
In focused ultrasound, ultrasound waves are concentrated on a single point in much the same way that light waves are condensed when they pass through a magnifying glass. The difference is that ultrasound waves can penetrate the body. Clinicians can tune the specific effect on tissue — producing everything from vibrations to heat — by manipulating the energy of the ultrasound waves.
“When I began as research director eight years ago, I provided seed grants to a number of people at UVA who were interested in focused ultrasound and discussed with others the value of incorporating focused ultrasound into their research,” Price says. “Those efforts have paid off. We now have a number of large-scale research projects and clinical trials underway. The momentum of our research will only grow over time.”
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Developing a Menu of Applications
As a treatment for cancer and other diseases, proponents of focused ultrasound point to three potential modes of action. First, focused ultrasound could replace radiation as a means to destroy tissue, either through thermal ablation or mechanical cavitation. In contrast to radiation, there is no limit to the number of times focused ultrasound can be administered. And because it has a tighter penumbra, clinicians can work out to the very margins of a tumor without destroying healthy tissue.
Second, focused ultrasound could be harnessed to improve drug and gene delivery, Price’s specialty. When used to agitate microbubbles of dissolved gases, focused ultrasound can create temporary pores in the blood-brain barrier and blood vessel walls, allowing drugs and genes access to targeted areas of the body. This is especially helpful for treating infiltrating tumors that cannot be totally resected like glioblastomas. Focused ultrasound can also be directed at specific locations, releasing therapeutics encapsulated in microbubbles and other carriers as they pass through the bloodstream. In both cases, focused ultrasound could give clinicians the ability to deliver agents exactly at the point need and nowhere else, lessening systemic side effects.
Finally, focused ultrasound, either through ablation or mechanical destruction, can be applied to augment immunotherapy. For instance, when focused ultrasound is used to ablate a tumor, the resulting heat shock promotes a heightened immune response, boosting the effectiveness of immunotherapeutics.
“Focused ultrasound has the potential to greatly expand and improve the options available to clinicians,” Price says. “At UVA, we are studying all three ways to apply focused ultrasound so that we can determine what might work best in a given situation.”
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Clinical trials to treat breast cancer and melanoma
UVA has organized a number of clinical trials to move these innovations to the bedside. It is the first institution in the world to combine focused ultrasound and immunotherapy to treat metastatic breast cancer. If successful, this trial will provide a new hope for patients diagnosed with this late-stage of the disease.
“Breast cancer cells can ride under the radar of the body’s immune system so that it is tolerated and allowed to grow,” explains the trial’s co-investigator David Brenin, MD, chief of breast cancer surgery at UVA and co-director of the UVA Breast Care Program.
Brenin and his collaborator, Patrick Dillon, MD, principal investigator for the trial, will partially ablate the breast cancer cells, stimulating a brisk immune response. At the same time, they will infuse the patient with an immunotherapy drug — Keytruda® — that checks the action of proteins that breast tumors generate to defeat the immune system.
“We hope the activated immune system will not only destroy any cancer cells at the local site, but also circulate throughout the rest of the body, recognizing and destroying cancer cells that have been deposited in distant sites such as the bones, lungs, or liver,” Dillon says. Brenin and Dillon are collaborating with Price and Tim Bullock, a researcher working at the intersection of focused ultrasound and immunotherapy, on the study. “Biopsies of the first patients show that there are T-cells — the immune systems killer cells — everywhere,” he says. “We are very hopeful.”
A second trial is being planned to use a similar strategy for patients with melanoma. UVA has also conducted clinical trials of focused ultrasound as a noninvasive, nondisfiguring replacement for surgery for treating uterine fibroids and breast fibroadenomas.
Becoming a mainstream therapy
Price points out that the applications of focused ultrasound that UVA is pioneering are reinforced by the strengths of the Department of Biomedical Engineering in MRI and ultrasound imaging. Both modalities can be used to direct the focused ultrasound beam. MRI can also be applied to monitor the temperature of tissue subjected to focused ultrasound. Professor Craig Meyer, an MRI expert, is currently developing an MRI system to create fast, three-dimensional temperature maps, an improvement over the information currently available.
“UVA has many of the elements needed to make focused ultrasound mainstream therapy for a variety of conditions,” Price says. “The momentum of our research will only grow over time.”
Message from the Chair
UVA leadership in focused ultrasound is not a coincidence. A local foundation with a celebrity board, the Focused Ultrasound Foundation, is dedicated to advancing this potential replacement for surgery and radiation. The University and the Commonwealth of Virginia contributed millions of dollars almost 10 years ago to create a Center of Excellence at UVA. And the School of Medicine assembled a core group of researchers investigating clinical applications to treat cancer, neurological conditions and other diseases.
The BME department has been instrumental to the University’s success. We have world-class expertise in the MRI and ultrasound imaging needed to guide focus ultrasound as well as a faculty member, Professor Richard Price, who has been exploring targeted drug delivery with focused ultrasound for more than a decade. As research director for the UVA Focused Ultrasound Center, Rich has been responsible for promoting the array of large-scale research projects and clinical trials now underway here.
It takes leadership, strategic vision, scores of committed people and sustained funding to establish a new therapeutic platform. We are fortunate to achieved this combination as we work to realize the promise of focused ultrasound.
Fred Epstein, Mac Wade Professor and Chair