Peripheral afferent neurons — nerves that send signals from all areas of the body to the central nervous system (brain and spinal cord) — are known to infiltrate and grow within malignant bone tumors called osteosarcomas, often accompanied by severe pain. In a primarily federally funded study published in today's issue of the Proceedings of the National Academy of Sciences of the United States of America (PNAS), a multicenter research team led by Johns Hopkins Medicine reports that two analgesic drugs, bupivacaine and rimegepant, which are used to inhibit the formation and functioning of these neurons, not only relieve tumor-associated pain in laboratory mice, but also slow the unchecked growth of the cancer.
The paper was previewed Oct. 21, 2025, and may be accessed here.
"Our findings suggest that these two medications — already approved by the U.S. Food and Drug Administration [FDA] for relieving nerve pain [bupivacaine] and migraines [rimegepant] — might one day be repurposed as anti-tumor therapies," says study lead author Sowmya Ramesh, Ph.D., a postdoctoral researcher in pathology at the Johns Hopkins University School of Medicine. "That's because our study shows that these drugs affect three proteins: calcitonin gene-related peptide [CGRP], tryptomyosin receptor kinase-A [TrkA] and nerve growth factor [NGF], inhibiting their neuron-to-tumor signaling and keeping them from stimulating innervation [supplying of nerves] and angiogenesis [blood vessel formation] in osteosarcomas."
"Later in our study, we saw that using these two drugs on mice with osteosarcoma-like tumors not only inhibits nerve and blood vessel formation in the tumors, but also impedes the cancer's growth and spread," she says. "The hope is that this finding may one day translate into a treatment for human osteosarcomas."
Ironically, limiting the effects of TrkA and NGF signaling is the opposite goal of previous research on the three proteins by Johns Hopkins Medicine's James Laboratory, the group leading the current study.
"In our past work, we showed in mice that NGF-TrkA signaling by peripheral neurons, which increases the sprouting of sensory nerves and blood vessels in bone, is critically important in fracture repair, so the aim there was to increase the amount of these proteins," says laboratory leader and senior study author Aaron James, M.D., Ph.D., professor of pathology at the Johns Hopkins University School of Medicine. "Now, instead, we want to curtail this peripheral nerve signaling to prevent innervation and angiogenesis in osteosarcomas and in turn, reduce or stop the tumor's growth and spread."
The initial step in the PNAS study was defining how sensory neurons help regulate the growth and spread of osteosarcomas. To do this, the researchers used mice with osteosarcoma-like tumors that were genetically modified to inhibit TrkA signaling activity.
"We found that the mice with inhibited NGF-TrkA signaling had markedly less nerve growth," explains Ramesh. "Additionally, a large number of the TrkA-inhibited mice showed slower overall tumor growth and spread, and prolonged survival."
According to study co-lead author Qizhi Qin, Ph.D., a postdoctoral fellow in the James Laboratory, the researchers also found that inhibition of TrkA activity led to a reduction in tumor-associated macrophages.
"These white blood cells, frequently found in osteosarcomas, can promote tumor growth, angiogenesis and cancer metastasis [spread to other parts of the body] by suppressing the immune system's ability to fight tumors and inducing resistance to chemotherapeutic drugs," she explains.
The researchers next examined tissues from human osteosarcomas, and found they all showed the effects of NGF-TrkA binding, namely the expected increased nerve and blood vessel growth.
"This suggests that in human osteosarcomas, what was seen in the mouse tumors — NGF-TrkA signaling resulting in increased innervation and angiogenesis — also leads to tumor growth and spread, and sarcoma-induced nerve pain," says James.
Samples of dorsal root ganglion (DRG) neurons — nerves along the spinal cord that are critical in transmitting signals from peripheral nerves to the central nervous system — from people with and without tumors also were studied. Upon reanalysis, the researchers found both CGRP activity and inflammation in the DRG neurons taken from patients who reported tumor-associated pain.
Having established that human osteosarcoma growth and spread, and osteosarcoma-associated pain, are both linked to CGRP-induced NGF-TrkA signaling activity, the researchers wondered if blocking CGRP might remediate both problems.
"We found in our mouse osteosarcoma model that both FDA-approved drugs, bupivacaine and rimegepant, reduced the amount of tumor-associated innervation and angiogenesis seen," says Ramesh.
Now that they have shown that peripheral sensory nerves are associated with osteosarcoma growth and spread, the researchers say that they'll next try to further define the mechanism by which neurons respond to the tumor and how neurons behave according to those responses.
Along with Ramesh, Qin and James, the members of the research team from the Johns Hopkins University School of Medicine are Mary Archer, Devadtta Balaji, Sam Bae, Leslie Chang, Masnsen Cherief, Mario Gomez-Salazar, Yun Guan, Zhao Li, Edward McCarthy, Neelima Thottappillil, Ankit Uniyal, Xin Xing, Mingxin Xu, Lingke Zhong and Manyu Zhu. Team members from other institutions are Carol Morris, Memorial Sloan Kettering Cancer Center; Thomas Clemens, University of Maryland School of Medicine; Khadijah Mazhar and Theodore Price, University of Texas at Dallas; Benjamin Levi and Monisha Mittal, University of Texas Southwestern; and Alexander Birbrair, University of Wisconsin-Madison.
Federal funding for the study includes three grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health (NIH): P01 AG066603, R01 AR079171 and R21 AR078919; two grants from the National Institute of Dental and Craniofacial Research at NIH: R01 DE031488 and R01 DE031028; two grants from the National Institute of Neurological Disorder and Stroke at NIH: NS110598 and NS117761; two grants from NIH: U19 NS130608 and R01 NS 11929; and a grant from the Department of Defense: USAMRAA HT9425-24-1-0051.
Non-federal support for the study includes grants from the Alex's Lemonade Stand Foundation, the American Cancer Society and the Maryland Stem Cell Research Foundation.
James is a paid consultant for Novadip and Lifesprout LLC. Guan is a principal investigator in a research grant from Medtronic Inc. and received a research award from BioTissue Inc. None of the other authors had any conflict-of-interest disclosures to report.
