While ultrasound technology may be best known for imaging, in recent years it’s been making its mark as a therapeutic option. Since Natasha Sheybani, a biomedical engineer at the University of Virginia (UVA), started working in the field as a graduate student, she’s seen focused ultrasound take off as a method to help treat everything from neurological disorders to cancer.

“There are over 100 clinical indications to date now for focused ultrasound technology. The little corner of the field I work in is only scratching the surface of all the potential that the technology has,” she said.

Sheybani, who started her research career at age 14 by calling labs at her local university, Virginia Commonwealth University, has been interested in drug delivery since her high school and undergraduate research experiences. Now, she leads her own research group at the University of Virginia where she uses focused ultrasound technology to help treat cancers that originate in or spread to the brain. As a new member of Forbes “30 under 30” list and the recipient of a prestigious NIH Director’s Early Independence Award, Sheybani is excited to translate focused ultrasound technology from preclinical models to human clinical trials for these difficult-to-treat cancers.

What is focused ultrasound technology?

We tend to think of ultrasound in the traditional sense of imaging, where it emits sound waves into the tissue, and then we collect images. But as it turns out, we can also use it to evoke really interesting biological effects that range from thermal to mechanical in nature. Much of this versatility is rooted in our ability to tune our acoustic exposure conditions and ultimately achieve different effects.

Put another way, if you've ever been out on a hot summer's day and used a magnifying glass with the light transmitting through it, you can burn a hole in a leaf. We’re doing the same thing but with sound waves instead of light. We don't have to burn the tissue. Focused ultrasound can also produce mechanical energy to destroy or manipulate tissue. For instance, I'm very interested in leveraging those mechanical properties for blood brain barrier disruption.

How does disrupting the blood-brain barrier with focused ultrasound help treat brain cancer?

By using focused ultrasound, we can open gaps in the blood-brain barrier in a localized manner to allow drugs to cross. A lot of researchers in the field think about this in the context of things like chemotherapy delivery, immunotherapy delivery, and even immunomodulation by acoustically shifting the immune cell populations within tumors.

I’m really interested in understanding what happens to the immune milieu both locally within the glioma as well as systemically. In my group’s recent paper in the Journal of Neuro-Oncology, we reported that focused ultrasound is not entirely quiescent (1). There are definitely some immunological effects that we gleaned purely from disrupting the blood-brain barrier. We saw a short-term increase in inflammatory effects in the brain tumors in mice administered focused ultrasound. My next question is how we can better leverage those effects to improve immunotherapy. The next step would be to design a system to combat the cancer in a way that synergizes well with the effects of the focused ultrasound. There's still so much we have to uncover in terms of immune modulation.

Can focused ultrasound also be used as a diagnostic tool?

There's emerging evidence spanning preclinical and clinical research that suggests that poking a brain tumor with mechanical or thermal focused ultrasound releases biomarkers into the blood. Those biomarkers can be analyzed with liquid biopsies, which are non-invasive and more repeatable than standard tissue biopsies, especially in the case of brain tumors, which are particularly challenging to access.

We're now looking at the possibility of using focused ultrasound to enable better biomarker assays of the blood. It's really compelling to think about how we can manage cancer with focused ultrasound from all of these different perspectives.

What scientific accomplishment are you most proud of so far?

When I was a graduate student, I studied breast cancer. One of my goals was to design a combinatorial paradigm involving focused ultrasound and a chemotherapy known as gemcitabine. Gemcitabine transiently inhibits a highly suppressive immune cell population known as myeloid-derived suppressor cells, which played a burdensome role in our preclinical breast cancer model. We had a hard time seeing the effects of the focused ultrasound in this model. We ultimately ended up designing this paradigm by combining focused ultrasound thermal ablation and gemcitabine. We showed that it’s underscored by specific mechanisms of adaptive immunity that, at least in part, seem to be driven by T cells (2).

Long story short, this paradigm was recently translated into a clinical trial that is ongoing here at UVA. If I had to point out any one thing that I'm proud of, it's the fact that we took a study all the way from the bench to the bedside while I was a grad student. One of the reasons I feel very fortunate being back at UVA now is that I'll get to connect with this trial going forward as these early-stage breast cancer patients undergo this focused ultrasound plus gemcitabine treatment.

What do you find most exciting about using focused ultrasound to study brain cancer?

This technology is non-invasive and non-ionizing. From the standpoint of how patients experience and interface with the technology, those two factors alone are huge. The versatility we can get from one technology makes me so excited about the future of focused ultrasound. The technology has really taken off clinically, so to see a pathway to translation, for me personally as a preclinical researcher, is also really exciting, especially in the glioblastoma space.

This interview has been edited for length and clarity.

References

1. Sheybani, N.D. et al. Profiling of the immune landscape in murine glioblastoma following blood brain/tumor barrier disruption with MR image-guided focused ultrasound. J Neurooncol  156, 109-122 (2022).
2.  Sheybani, N.D. et al. Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity. Journal for ImmunoTherapy of Cancer  8, e001008 (2020).