Neurofibromatosis type 2 (NF2), also known as NF2-related schwannomatosis, is a rare genetic condition that can be very debilitating, says Jignesh Tailor, MD, PhD.
Affecting about 1 in 25,000 people worldwide, NF2 causes tumors to grow around nerves, often in the brain and spine. NF2 can affect both children and adults, but symptoms typically appear during adolescence.
Several types of tumors are associated with NF2, including ependymoma, which tends to develop within the spinal cord. These tumors are often non-cancerous, but because of where they grow, they can cause serious problems with muscle strength, sensation, gait and balance.
“Ependymomas can lead to paralysis,” said Tailor, assistant professor of neurological surgery at the Indiana University School of Medicine and a pediatric neurosurgeon at Riley Hospital for Children in Indianapolis. “It can lead to weakness and loss of sensation. A lot of people end up wheelchair bound, as they progressively lose all function in their arms and legs.”
There is currently no effective medical therapy for spinal ependymoma, Tailor said, and surgical removal of these tumors is associated with high morbidity and mortality.
“You’re stuck between a rock and a hard place,” he said. “The ideal way to manage this is to treat these lesions early with medication, but we have limited drugs to use at this point.”
Tailor is hoping to get one step closer to overcoming this barrier for children with NF2-related schwannomatosis. He received a Mentored Clinical Scientist Research Career Development Award from the National Institute of Neurological Disorders and Stroke to study the role of NF2 gene mutation in neural stem cell differentiation failure and tumorigenesis.
“We’re specifically looking at how NF2 gene loss affects the developing nervous system, and how that mutation causes cells to deviate away from their normal trajectory, causing differentiation failure,” Tailor said. “Normal cells are primed to develop into neurons and glia, but some of these stall — they just don’t form those normal cell types. Some of these cells don’t know what to do so they just continue to grow, and that forms a tumor like ependymoma.”
Most spinal ependymoma tumors have mutations in both copies of the NF2 gene, and patients with NF2-related schwannomatosis are predisposed to this type of tumor.
“This is a very understudied area,” Tailor said. “A lot of focus has historically been on other types of brain tumors, like meningiomas and schwannomas. We need better models of spinal ependymoma to identify drug targets.”
In his preliminary studies, Tailor identified novel dysregulated radial-glia like cells derived from human stem cells that fail to differentiate normally in the setting of NF2 loss.
The grant will expand Tailor’s ongoing research, with the goal of discovering new therapeutics that could move into clinical trials to help people living with the condition.
“I have the benefit of seeing those patients in clinic,” Tailor said. “It’s rewarding for me to study this, especially in the early stages, and to have an opportunity to identify a treatment that could prevent these tumors from growing.
“That’s what motivates me. I love operating, but it’s not necessarily the best way to manage a lot of these lesions. If I’m able to identify a less-risky way to manage it, I think that would be in the best interest of patients.”
Tailor will accomplish this work under the mentorship of D. Wade Clapp, MD, a world-renowned expert in neurofibromatosis, and Mitesh V. Shah, MD, chair of the Department of Neurological Surgery at the IU School of Medicine.
Clapp is the Richard L. Schreiner Professor of Pediatrics and the chair of the Department of Pediatrics at the IU School of Medicine; he is also the physician-in-chief for Riley Hospital for Children. Among his many accolades, Clapp’s research has been internationally acclaimed and has resulted in several clinical trials.
Shah is a professor of neurological surgery, the Paul B. Nelson Endowed Chair and co-director of the IU Health-IU School of Medicine Neuroscience Institute. Shah treats a wide range of conditions and diseases, and his neurosurgical observations and investigations in neuro-oncology are documented in numerous peer-reviewed publications.
“Dr. Clapp played a big role in helping me get this award,” Tailor said. “He’s a great mentor. We’re very privileged to have him at the IU School of Medicine.”
Tailor, who joined the IU School of Medicine in 2021 and serves as surgical director of pediatric neuro-oncology at Riley Hospital, said he felt honored to receive the grant at this point in his career.
“It’s an important landmark for any scientist, particularly surgeon-scientists,” Tailor said. “Securing this grant also speaks volumes to the academic mission of our department and Dr. Shah’s leadership.”
With support of the grant, Tailor will receive additional experience and training in advanced cell engineering, single cell analytics and kinome profiling for drug discovery.
“This will allow me to develop certain expertise in techniques that are new. For example, we’re going to be doing a lot of kinome profiling, which is a way to identify drug targets in our models, and that’s something that I’ve not done before,” Tailor said. “I’ll be learning a lot, and that’s ultimately the goal, to keep building the lab and continuing to grow.”
Tailor’s long-term career goal is to develop more effective treatments for brain and spinal cord tumors in children and young adults with cancer predisposition syndromes. He hopes to become an independent investigator directing a research program in brain and spinal cord tumorigenesis.
