Dr. Woodworth is currently an Assistant Professor of Neurosurgery, Anatomy and Neurobiology at the University Of Maryland School Of Medicine and the Director of Neurosurgical Oncology at the University of Maryland (UM) Greenebaum Cancer Center. He completed medical school in 2005 and neurosurgery residency in 2012, both at Johns Hopkins. Prior to my medical and neurosurgery training, he trained and worked as an organic chemist at Tufts University and Pfizer - Drug Discovery Division. He was a post-doctoral research fellow in Neuro-Oncology through the National Cancer Institute-funded T32 Program in Nanotechnology for Cancer Medicine. Dr. Woodworth's long-term goal is to become an independently- funded neurosurgeon-scientist, leveraging the operating room as a portal for discovery and an opportunity for therapeutic delivery. He is working to advance Translational Neuro-Oncology with a research focus on delivering therapeutics to brain-invading, unrespectable cancer cells. Towards this goal, he aims to improve outcomes for patients with central nervous system tumors through innovative research in drug formulation, delivery, and testing. He will enhance his research career development through the following short-term (3-5 year) goals and objectives: (1) Study the cellular and structural targeting strategies for enhancing glioblastoma (GBM) therapeutics;specifically, explore the TWEAK-Fn14 signaling pathway, (2) Investigate advanced local and other delivery systems for invasive brain cancer;particularly, examine new convection enhanced and systemic approaches, such as magnetic resonance imaging guided focused ultrasound (MRgFUS), and (3) Understand and analyze the relative merits and limitations of patient- derived xenograft and transgenic rodent GBM models. To accomplish these short- and long-term career development goals, Dr. Woodworth has enlisted three outstanding mentors with expertise in these areas and plans to integrate these interactions with specific educational activities in related areas. These mentors are: Jeff Winkles, Ph.D. (primary mentor), Justin Hanes, Ph.D. (co-mentor), and Nhan Tran, Ph.D. (co-mentor). Research activities will be complemented throughout the training period with clinical activity caring for patients with benign and malignant CNS tumors with 50% effort. This equal contribution of clinical and scientific activities will enable continued growth and evolution as a neurosurgeon including maintaining surgical skills, remaining abreast of neurosurgical advances and developments, and relating the research efforts to current clinical dilemmas. The administrative leadership of and clinical partners within the Neurosurgery Department are strongly committed to ensuring this protected time. Dr. Woodworth's laboratory is joint-funded by the department, the School of Medicine and grants from the NIH Neurosurgeon Research Career Development Program and the Passano Foundation. The support includes a newly renovated 800ft2 laboratory space in the Bressler Research Building within the Greenebaum Cancer Center and directly connected to the main University of Maryland Hospital building. The overall experimental design and rationale for this project is based on the observation that larger- than-expected particles with specially engineered surface coatings can penetrate rapidly within brain tissue. These particles have been termed 'brain-penetrating nanoparticles'(BPN) and evidence strongly suggests that these large, non-adhesive particles will enable improved dispersion in brain tissue, controlled drug release, and targeting to brain-invading cancer cells. Two members of the mentoring team (JW, NT) have worked together for a number of years on the cell-surface receptor Fn14 and they were the first investigators to report that Fn14 gene expression is upregulated on invading GBM cells in vivo. These findings create a promising opportunity to develop Fn14-targeted BPNs that are anticipated to improve therapeutic delivery and efficacy with less toxicity. The overall hypothesis is that BPNs will enable improved therapeutic delivery to and efficacy against invasive brain tumors;this will be tested using Fn14-targeted BPNs loaded with promising chemotherapeutic agents delivered via a local convection-enhanced approach in an invasive patient-derived xenograft model.
Three Specific Aims are proposed for this project: (1) Formulate and characterize nanoparticles with and without Fn14-specific targeting agents, (2) Evaluate the tissue distribution and cell-targeting efficiency of optimized nanoparticle formulations following convection enhanced local delivery (CED), and (3) Assess the therapeutic efficacy of drug-loaded nanoparticles administered via CED against and in combination with the standard GBM chemotherapeutic agent temozolomide using an invasive, patient-derived tumor model.
Brain cancer is the leading cause of cancer related deaths in patients younger than 35 years. Malignant glioma is the most common and deadly primary brain cancer, largely due to brain-invading tumor cells that prevent complete surgical removal and lead to recurrence - often with devastating neurological consequences. The aim of this project is to develop advanced therapeutic delivery systems that enable improved drug dispersion, targeting to invading cancer cells, and thereby, greater drug efficacy while minimizing toxicity.
|Perez, J G; Tran, N L; Rosenblum, M G et al. (2016) The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics. Oncogene 35:2145-55|
|Hersh, David S; Nguyen, Ben A; Dancy, Jimena G et al. (2016) Pulsed ultrasound expands the extracellular and perivascular spaces of the brain. Brain Res 1646:543-50|
|Hersh, David S; Kim, Anthony J; Winkles, Jeffrey A et al. (2016) Emerging Applications of Therapeutic Ultrasound in Neuro-oncology: Moving Beyond Tumor Ablation. Neurosurgery 79:643-654|
|Hersh, David S; Wadajkar, Aniket S; Roberts, Nathan B et al. (2016) Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier. Curr Pharm Des 22:1177-93|
|Schneider, Craig S; Bhargav, Adip G; Perez, Jimena G et al. (2015) Surface plasmon resonance as a high throughput method to evaluate specific and non-specific binding of nanotherapeutics. J Control Release 219:331-44|
|Schneider, Craig S; Perez, Jimena G; Cheng, Emily et al. (2015) Minimizing the non-specific binding of nanoparticles to the brain enables active targeting of Fn14-positive glioblastoma cells. Biomaterials 42:42-51|
|Nance, Elizabeth; Timbie, Kelsie; Miller, G Wilson et al. (2014) Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound. J Control Release 189:123-32|
|Kim, Anthony J; Woodworth, Graeme F; Boylan, Nicholas J et al. (2014) Highly compacted pH-responsive DNA nanoparticles mediate transgene silencing in experimental glioma. J Mater Chem B Mater Biol Med 2:8165-8173|