A study co-authored by National Foundation for Cancer Research Fellow Dr. Rakesh Jain hints that adding the cancer drug crizotinib to the radiation therapy for tumors associated with neurofibromatosis 2 (NF2) may lessen the hearing loss that often precipitates from radiotherapy.
Although not a cancer, NF2 is characterized by benign tumors that develop throughout the nervous system. Specific to this study, these are intracranial tumors, called vestibular schwannomas, that arise on the eighth cranial nerve, a critical information pathway from the ear to the brain. NF2-related interference to this nerve typically leads to profound or total hearing loss by middle age. Previous research done in 2016 concerning application of the drug bevacizumab initially showed positive results in patients’ hearing, but later was found to be only a temporary effect.
However, the bevacizumab study revealed better hearing improvement in NF2 patients who had lower circulating levels of hepatocyte growth factor (HGF), which is known to interact with the cMET oncogene. Pathways controlled by HGF are known to interact with pathways controlled by the blood vessel growth factors in schwannomas. These and other studies suggested that the HGF-cMET pathway may play a role in schwannoma progression, response to treatment and hearing loss.
Those results led researchers to test the use of crizotinib to block cMET signaling in two mouse models—the standard model in which NF2 cells are injected into the sciatic nerve and a new model that implants schwannoma cells into the brain adjacent to the eighth cranial nerve. In both, the use of crizotinib to block the HGF-cMET pathway improved treatment response by enhancing radiation-induced DNA damage, significantly reducing tumor growth and extending survival. Genetic knockdown of cMET had similar results, and experiments using the novel mouse model showed that blocking cMET itself did not adversely affect the animals’ hearing.
“With this new culture model we can screen libraries of drugs for anti-tumor activity,” says Jain, who is also the Cook Professor of Radiation Oncology at Harvard Medical School.
“These methods and tools will address a major bottleneck in the NF2 field by providing robust, expandable and biologically diverse cellular models that recapitulate the defining features of this and other human diseases,” he adds.
Because the Food and Drug Administration already approved crizotinib, Jain and the other study team members hope these findings can move from models to clinical trials and then on to the public more speedily.
- Jain, Rakesh H., et al. Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models. (February, 2018) Proceedings of the National Academy of the United States of America. https://doi.org/10.1073/pnas.1719966115