Researchers with the University of Cincinnati and Johns Hopkins Medicine developed a potential treatment for brain cancer that uses nanofibers embedded with a combination of drugs that work in concert to target tumors.

The drugs proved more effective in combination than when administered alone and can provide both immediate and long-lasting doses to kill cancer cells.

Lead author Daewoo Han, an assistant professor in UC’s College of Engineering and Applied Science, and UC Distinguished Research Professor Andrew Steckl incorporated the drugs into electrospun fiber membranes, creating a nanofiber drug delivery system. Steckl’s NanoLab at the University of Cincinnati is a leading developer of this technology that uses an electric field to create a multilayered fiber mesh for drug delivery, among other uses.

“This combination is pretty powerful,” Steckl said.

Glioblastoma is the most common and aggressive form of brain cancer in adults. Researchers at UC and Johns Hopkins found that the three federally approved drugs used to treat glioblastoma (temozolomide, acriflavine and PT2385) work better in combination than they would alone, a pharmaceutical phenomenon called synergism.

“When you add them together, three things can happen,” Steckl said. “The combination is negative; the effect is additive, like one plus one equals two; or it’s synergistic, which is like one plus one equals three.”

The study was published in the journal ACS Biomaterials Science & Engineering. The research was supported with a grant from the National Institutes of Health.

Steckl said glioblastoma is extremely difficult to treat because its heterogeneous cells allow for mutations that help the cancer evade treatment.

“It’s tough to control,” Steckl said. “It comes in through the window and when you close the window, it comes through the door. And when you close that, it comes through the chimney.”

Glioblastoma also has high recurrence. And the blood-brain barrier limits the effectiveness of other traditional chemotherapies.

“Our NanoMesh system was designed to solve these issues by enabling localized long-term delivery of multiple synergistic drugs directly at the tumor site after surgery,” UC’s Han said.

UC researchers worked with a team at Johns Hopkins Medicine, including Betty Tyler, a professor of neurosurgery, and postdoctoral researcher Hasan Slika. Tyler said researchers are looking to attack the disease with combinations of therapies.

“Unfortunately, cancers know how to pivot to evade therapeutic treatment,” she said. “So we’re approaching treatment multidimensionally.”

Tyler has helped develop other cutting-edge therapies now commonly used to treat cancer.

“Current therapies have increased patient survival and given them more birthdays,” she said. “But we’re still working on improving options.”

In animal trials, all untreated mice with glioblastoma died within 19 days. But a majority of mice treated with the three-layer nanofiber mesh survived twice as long. And 40% survived past the 120-day conclusion of the experiment in a plateau that stretched for more than 80 days.

Han said using electrospun fiber mesh, doctors can precisely control the dosage and release and the implant geometry, which contribute to its effectiveness. And just as the blood-brain barrier protects the brain from toxins, the barrier also protects the body from the toxic side effects of the medicine applied to the brain, Han said.

UC researchers are now working on optimizing the long-term release of medicines using advanced nanofiber structures. And the delivery system has broad potential in applications for other difficult-to-treat diseases, Han said.

“What’s next will be very exciting,” Han said. “Our ultimate goal is moving forward to a clinically translatable system that improves both survival and quality of life for patients with difficult-to-treat cancers, including glioblastoma.”

Journal

ACS Biomaterials Science & Engineering

Funder

NIH/National Institutes of Health

DOI

10.1021/acsbiomaterials.5c01482

The research focuses on peripheral afferent neurons, specialized nerve fibers responsible for transmitting sensory information from body tissues to the central nervous system. These neurons are known to invade osteosarcoma tumors, where their interaction creates a microenvironment that not only exacerbates pain but also supports tumor innervation and angiogenesis, fostering unchecked malignancy growth. Using sophisticated murine models genetically engineered to suppress key neuron growth pathways, the study uncovers the pivotal role played by proteins—nerve growth factor (NGF), its receptor tropomyosin receptor kinase-A (TrkA), and calcitonin gene-related peptide (CGRP)—in mediating this pathological crosstalk.

The authors demonstrate that pharmacological blockade of NGF-TrkA signaling via the application of bupivacaine and rimegepant—drugs already sanctioned by the FDA for nerve pain and migraine management, respectively—substantially diminishes tumor-associated nerve sprouting as well as the vascular networks vital for tumor sustenance. This suppression not only alleviates the debilitating pain affecting osteosarcoma patients but crucially retards tumor proliferation and metastatic dissemination. The findings redefine the therapeutic landscape, underscoring the potential of targeting peripheral neurobiology to combat bone cancer.

Intriguingly, the team’s previous research had established that enhancement of NGF-TrkA signaling facilitates bone fracture repair by promoting nerve and blood vessel growth. This new study, however, reveals a paradox wherein the very pathway that aids skeletal healing becomes hijacked by malignant cells to foster their expansion. Aaron James, M.D., Ph.D., senior author and professor of pathology at Johns Hopkins, emphasizes that therapeutic strategies must therefore be context-dependent, shifting from stimulation in regenerative settings to inhibition in oncogenic ones.

Using genetically modified mice lacking functional TrkA signaling in sensory neurons, the team showed a marked reduction in tumor innervation and angiogenesis compared to controls. These TrkA-deficient mice exhibited slower tumor growth rates and extended survival, reinforcing the causal link between peripheral nerve activity and osteosarcoma pathogenesis. Beyond the neural landscape, the study noted a concomitant decline in tumor-associated macrophages—immune cells that contribute to a pro-tumor microenvironment by suppressing immune responses and aiding resistance to chemotherapy.

Human tumor samples echoed the murine findings by displaying increased expression of NGF-TrkA signaling components correlated with extensive nerve and vessel growth within osteosarcomas. This correlation validates the translational relevance of the mouse model and supports the notion that peripheral nerves actively shape tumor behavior in patients. Further analysis of dorsal root ganglion neurons — integral to relaying sensory signals from peripheral tissues — from individuals experiencing tumor-related pain revealed elevated CGRP activity alongside inflammatory markers, reinforcing the signaling axis as a candidate for therapeutic intervention.

Building upon these insights, the researchers administered bupivacaine and rimegepant to their osteosarcoma-bearing mice, observing significant reductions in neural and vascular tumor infiltration. These drugs, by disabling CGRP and NGF-TrkA signaling pathways, disrupt the neuron-to-tumor communication loop that amplifies malignancy. Consequently, treated mice manifested reduced tumor burden and decreased nociceptive behavior, suggesting dual benefits in cancer control and pain management.

The study’s revelation that peripheral sensory neurons are indispensable components in osteosarcoma development and symptomatology shifts paradigms in cancer biology. It unites neurobiology with oncology in a deeply mechanistic framework, illustrating how tumors co-opt physiological nerve signaling pathways to orchestrate their own growth niches. Future research aims to delineate the molecular underpinnings of neuron-tumor interactions further, potentially identifying new molecular targets alongside TrkA and CGRP to interrupt this pathogenic dialogue.

Funding for this research was provided by an extensive array of federal sources including multiple grants from the National Institutes of Health—specifically the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Neurological Disorders and Stroke, and the National Institute of Dental and Craniofacial Research—as well as support from the Department of Defense and prominent cancer and stem cell research foundations. Collaborative contributions extended across Johns Hopkins, Memorial Sloan Kettering Cancer Center, University of Maryland, University of Texas at Dallas, University of Texas Southwestern, and University of Wisconsin-Madison, embodying a truly multidisciplinary approach.

Beyond its scientific novelty, this work carries profound clinical implications. Current osteosarcoma treatments often involve aggressive surgical interventions and chemotherapy with limited success against metastatic disease and nerve pain. By repurposing already-approved medications that target nerve-cancer interactions, clinicians may soon have new tools to both stanch tumor growth and improve quality of life for patients suffering from severe cancer-induced pain. This study thus paves the way for translational efforts aiming to bridge basic discoveries with concrete therapeutic strategies.

Ultimately, the research underscores the intricate interplay between the nervous system and cancer biology, revealing peripheral neurons as key facilitators of malignancy rather than mere bystanders. By targeting this critical nexus with analgesic drugs, the field may witness the emergence of novel, less toxic therapeutic paradigms that leverage the body’s own signaling machinery to combat cancer.

Subject of Research: Interaction of peripheral sensory neurons with osteosarcoma tumor growth and associated pain mechanisms

Article Title: Peripheral sensory nerve signaling blockade impedes osteosarcoma growth and relieves tumor-associated pain

News Publication Date: October 28, 2025

Web References: https://doi.org/10.1073/pnas.2500161122

Image Credits: Sowmya Ramesh, Johns Hopkins Medicine

Keywords: Cancer, Bone cancer, Osteosarcoma, Peripheral nerves, NGF-TrkA signaling, Calcitonin gene-related peptide, Tumor innervation, Angiogenesis, Pain management, Bupivacaine, Rimegepant