Following the University of Maryland Medical System’s recent announcement that they are beginning the first US focused ultrasound clinical trial for patients with glioblastoma (GBM), we interviewed the study’s principal investigator (PI), neurosurgeon Graeme Woodworth, MD. Dr. Woodworth is Professor of Neurosurgery at the University of Maryland School of Medicine and Director of its Brain Tumor Treatment & Research Center. He is researching the use of focused ultrasound to open the blood-brain barrier to provide treatment options for patient with brain tumors (both glioma and metastatic) and other brain diseases. A member of the Foundation’s GBM consortium, Dr. Woodworth also serves on our Research Advisory Committee, a group tasked with ensuring that the External Research Awards Program supports catalytic research, creates awareness of focused ultrasound technology and techniques, and advances innovative clinical applications of focused ultrasound.
Q&A with Graeme Woodworth, MD
Focused Ultrasound Work
When and how did you get interested in focused ultrasound?
During my neurosurgery and research fellowship training, I met Rich Price from the University of Virginia and Victor Frenkel, then at the National Cancer Institute. I learned from them about new and potential applications for ultrasound, beyond those used in the hospital and neurosurgical operating room, such as drug delivery and stem cell homing.
What are your areas of interest in FUS?
My research efforts focus on improving treatments for unresectable, brain-invading tumor cells that cause neurological injury and contribute to GBM recurrence. Focused ultrasound offers the potential to localize acoustic energy to these cells and invaded brain regions to improve drug delivery, modulate immune function, and allow other potential therapeutic effects.
What mechanisms and clinical indications do you study?
We are working to better understand the interstitial and immunological effects of blood-brain barrier (BBB) disruption for treating brain tumors. Our team is also interested in using ultrasound to prime tumor tissues for nanoparticle-enhanced stem cell delivery.
What is the goal of your work?
Our primary goal is to improve outcomes for patients with malignant brain tumors. In this work, we aim to leverage and study the diverse effects of focused ultrasound to improve treatments for these tumors.
What are your funding sources?
We have funding from the American Cancer Society, the National Institutes of Health (NIH), and some seed funding from the University of Maryland. We are also interested in expanding partnerships with industry.
Who are your team members?
Here at the University of Maryland, our brain research team includes neurosurgeon Howard Eisenberg, MD, neuroradiologists Dheeraj Gandhi, MD and Elias Melhem, MD, radiology scientist/imaging expert Rao Gullapalli, PhD, ultrasound biologist Victor Frenkel, PhD, nanoparticle expert Anthony Kim, PhD, cancer biologist Jeffrey Winkles, PhD, and cancer immunologist Eduardo Davila, PhD. We have multiple talented students and post-doctoral researchers actively working on focused ultrasound-related projects.
We also work with Joe Frank, MD, at the NIH National Cancer Institute, who is an expert in ultrasound, MRI, molecular and cellular imaging, and cellular therapy.
Who are your other external collaborators?
We have a collaborative clinical trial with Insightec and are working in collaboration with the group at the University of Toronto, which includes Kullervo Hynynen, PhD, Nir Lipsman, MD, PhD, and their focused ultrasound teams at Sunnybrook Research Institute.
We are also expanding our collaborations related to ongoing FDA-approved clinical trials, including Alex Golby, MD, PhD, and Nathan McDannold, PhD, at Harvard/Brigham and Women’s Hospital.
What are your greatest achievements? Any major disappointments?
To date the greatest achievement has been designing and implementing the first two FDA-approved clinical trials of focused ultrasound for BBB disruption in patients with GBM. These accomplishments were achieved through a close partnership with Insightec, Inc. For disappointments, I would say nothing out of the ordinary.
What do you see as impediments to your success?
Our greatest variables in determining future success are consistent funding for projects and outstanding personnel to complete and expand the work.
What is on your research wish list?
Funding and outstanding personnel as noted earlier.
Does the Focused Ultrasound Foundation play a role in your work?
I have contributed to the Foundation’s immunomodulation consortium project, and the University of Maryland is one of the Foundation’s Centers of Excellence. I also received a grant from the Foundation in 2016 to study immunomodulation for GBM.
How many patients have you treated?
We have used focused ultrasound to treat many patients with essential tremor and Parkinson’s disease. Our goal for this year is to begin enrolling patients with glioblastoma in the BBB clinical trials.
Do you have any patient care highlights?
One of our patients, Kimberly Spletter, has an inspiring story related to Parkinson’s disease, and I have seen quite remarkable improvements in the lives of several of our patients with essential tremor.
What comes next?
We are excited to begin enrolling patients in the two brain tumor focused ultrasound clinical trials. The first study to begin enrolling patients will focus on BBB disruption prior to surgery and will enable histological study of the focused ultrasound-treated tumor tissues. The second study will superimpose on the current standard of care chemotherapy, temozolomide. In that study, focused ultrasound will be used to open the BBB at the beginning of each week of chemotherapy over a 6-month period.
FDA Approves US Blood-brain Barrier Study for Glioblastomas December 2017
GBM Consortium Tests Focused Ultrasound Immunomodulation Parameters October 2016
University of Maryland Center of Excellence Dedicated to Brain Research September 2016
BBB Research Teams November 2015
University of Maryland to Become Major Focused Ultrasound Neuroscience Research Center September 2014
Key Focused Ultrasound Publications
Hersh DS, Anastasiadis P, Mohammadabadi A, Nguyen BA, Guo S, Winkles JA, Kim AJ, Gullapalli R, Keller A, Frenkel V, Woodworth GF. MR-guided transcranial focused ultrasound safely enhances interstitial dispersion of large polymeric nanoparticles in the living brain. PLoS ONE 2018 13(2): e0192240. PMID: 29415084
Hersh DS, Kim AJ, Winkles JA, Eisenberg HM, Woodworth GF, Frenkel V. Emerging Applications of Therapeutic Ultrasound in Neuro-oncology: Moving Beyond Tumor Ablation. Neurosurgery 2016 Aug 22. PMID: 27552589
Dancy JG, Wadajkar AS, Schneider CS, Mauban JR, Goloubeva OG, Woodworth GF, Winkles JA, Kim AJ. Non-specific binding and steric hindrance thresholds for penetration of particulate drug carriers within tumor tissue. J Control Release 2016 Jul 25;238:139-148. PMID: 27460683
Hersh DS, Nguyen BA, Dancy JG, Adapa AR, Winkles JA, Woodworth GF, Kim AJ, Frenkel V. Pulsed ultrasound expands the extracellular and perivascular spaces of the brain. Brain Res 2016 Jun 28. pii: S0006-8993(16)30464-4. PMID: 27369449
Hersh DS, Wadajkar AS, Roberts NB, Perez JG, Connolly NP, Frenkel V, Winkles JA, Woodworth GF, Kim AJ. Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier. Curr Pharm Des 2015 Dec 21. PMID: 26685681
Nance EA, Timble K, Miller, W, Song J, Louttit C, Klibanov A, Shih T, Swaminathan G, Tamargo RJ, Woodworth GF, Hanes J, Price RJ. Noninvasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound. J Control Release 2014, 189: 123-32. Received the Jorge Heller Outstanding Paper Award, Controlled Release Society 2015 (PMCID: 4125545)