Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 9, Pages E2077-E2084Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1719966115
Keywords
schwannoma; cMET blockade; radiation; hearing test
Categories
Funding
- Department of Defense New Investigator Award [W81XWH-16-1-0219]
- American Cancer Society Research Scholar Award [RSG-12-199-01-TBG]
- Children's Tumor Foundation Drug Discovery Initiative
- Ira Spiro Award
- National Natural Science Foundation of China [81372715, 81502657]
- National Cancer Institute Outstanding Investigator Award [R35-CA197743]
- Lustgarten Foundation
- Ludwig Center at Harvard
- National Foundation for Cancer Research
- Gates Foundation
- National Institute on Deafness and Other Communication Disorders Grant [R01DC015824]
- Department of Defense [W81XWH-14-1-0091]
- Bertarelli Foundation
- Nancy Sayles Day Foundation
- Lauer Tinnitus Research Center
- [P01-CA080124]
- [P50-CA165962]
- [R01-CA129371]
- [R01-CA208205]
- [U01-CA 224348]
Ask authors/readers for more resources
Neurofibromatosis type II (NF2) is a disease that needs new solutions. Vestibular schwannoma (VS) growth causes progressive hearing loss, and the standard treatment, including surgery and radiotherapy, can further damage the nerve. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. The mechanisms underlying deafness in NF2 are still unclear. One of the major limitations in studying tumor-induced hearing loss is the lack of mouse models that allow hearing testing. Here, we developed a cerebellopontine angle (CPA) schwannoma model that faithfully recapitulates the tumor-induced hearing loss. Using this model, we discovered that cMET blockade by crizotinib (CRZ) enhanced schwannoma radiosensitivity by enhancing DNA damage, and CRZ treatment combined with low-dose radiation was as effective as high-dose radiation. CRZ treatment had no adverse effect on hearing; however, it did not affect tumor-induced hearing loss, presumably because cMET blockade did not change tumor hepatocyte growth factor (HGF) levels. This cMET gene knockdown study independently confirmed the role of the cMET pathway in mediating the effect of CRZ. Furthermore, we evaluated the translational potential of cMET blockade in human schwannomas. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared with normal nerves, which correlated with tumor growth and cyst formation. Using organoid brain slice culture, cMET blockade inhibited the growth of patient-derived schwannomas. Our findings provide the rationale and necessary data for the clinical translation of combined cMET blockade with radiation therapy in patients with NF2.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available