ABSTRACT
Neurofibromatosis type 2 (NF2) is a profoundly devastating tumor predisposing syndrome characterized by
multiple nervous system tumors that cause substantial debility for patients. The hallmark of NF2 is bilateral
vestibular schwannomas (VS) which cause hearing loss, imbalance, brainstem compression and even death.
Both NF2-associated and sporadic VS can develop aggressive cystic degeneration which result in rapid
neurologic decline. There are no FDA-approved pharmacotherapies against cystic VS and surgery is the only
treatment. However, surgical outcomes are highly variable, and surgery carries considerable morbidities
including deafness, facial paralysis, brain injury and incomplete resection, due to significant peri-tumoral
adhesions and reliance on imprecise visual cues during tumor dissection. Efforts are needed to identify
biomarkers to classify aggressive VS and develop intraoperative tools to detect tumor cells, visualize the
interface between tumor and cochlear/facial cranial nerves and improve the accuracy of surgical resection.
This K08 career development award is designed to launch the principal investigator’s career as an
independent surgeon scientist, whose goal is to understand mechanisms that underlie VS growth and cystic
degeneration, identify molecular biomarkers to classify disease, and leverage nanotechnology tools to improve
the precision of tumor surgery. The PI’s mentor (Krystof Bankiewicz) is a leader in delivering therapeutics to
the central nervous system and translational research. The PI’s co-mentor (Long-Sheng Chang) is an expert in
studying the NF2 tumor suppressor gene function in VS. Additional mentorship is provided by a research
advisory committee of experts in nanoparticle delivery (Yizhou Dong), matrix metalloprotease and extracellular
matrix biology (Jennifer Leight), and skull base surgery (Oliver Adunka), along with didactics and workshops at
the Ohio State University and nationally.
Previously, the PI utilized primary human VS cultures to develop nanoparticles that target VS and identified
a matrix metalloproteinase whose activity was associated with poor surgical outcomes in VS. The proposed
study will: 1) systematically identify proteases dysregulated in VS through spatial transcriptomic profiling; 2)
engineer a library of nanomaterials to rapidly quantify VS protease activity and establish an activity-based
tumor-classifying biomarker; 3) develop protease-sensing, tumor-targeted nanoparticles. Results from this
work will elucidate mechanisms that regulate VS behavior and establish tools to enhance the accuracy of
surgical resection, which could ultimately reduce treatment-associated morbidity, preserve cranial nerve
function and improve outcomes for patients with this devastating disease. Furthermore, the principal
investigator will obtain the training needed to transition into an independent physician scientist focusing on
using nanotechnology to translate biological discoveries into new diagnostics and therapeutics for VS and NF2.
