机构：[a]Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114[b]Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China重点科室诊疗科室神经外科神经外科首都医科大学附属天坛医院[c]Eaton Peabody Laboratories, Department of Otolaryngology, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA 02114[d]Molecular Pathology Division, Massachusetts General Hospital, Boston, MA 02114[e]Division of Biostatistics, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114[f]Department of Neurology, Massachusetts General Hospital, Boston, MA 02114[g]Cancer Center, Massachusetts General Hospital, Boston, MA 02114[h]Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430023 Hubei, China.[i]Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, 100730 Beijing, China.其他中心耳鼻咽喉头颈外科中心首都医科大学附属同仁医院[j]Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, China.
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.
基金：
We thank Shan Min Chin, Anna Khachatryan,
and Carolyn Smith for their superb technical support; Sylvie Roberge and
Dr. Peigen Huang for assistance in animal studies, tumor implantation, and
cranial window generation; and Meenal Datta for editorial help with the
manuscript. This study was supported by Department of Defense New Investigator
Award W81XWH-16-1-0219 (to L.X.); American Cancer Society Research
Scholar Award RSG-12-199-01-TBG (to L.X.); the Children’s Tumor Foundation
Drug Discovery Initiative (L.X.); the Ira Spiro Award (to L.X.); National Natural
Science Foundation of China Grant 81372715 (to P.L.); Grants P01-CA080124,
P50-CA165962, R01-CA129371, R01-CA208205, and U01-CA 224348 (to R.K.J.);
National Cancer Institute Outstanding Investigator Award R35-CA197743
(to R.K.J.); the Lustgarten Foundation (R.K.J.); the Ludwig Center at Harvard
(R.K.J.); the National Foundation for Cancer Research (R.K.J.); the Gates
Foundation (R.K.J.); National Institute on Deafness and Other Communication
Disorders Grant R01DC015824 (to K.M.S.); Department of Defense
Grant W81XWH-14-1-0091 (to K.M.S.); the Bertarelli Foundation (K.M.S.);
the Nancy Sayles Day Foundation (K.M.S.); the Lauer Tinnitus Research Center
(K.M.S.); and National Natural Science Foundation of China Grant
81502657 (to Y.c.Z.).
第一作者机构：[a]Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114[h]Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430023 Hubei, China.
共同第一作者：
通讯作者：
通讯机构：[a]Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
推荐引用方式(GB/T 7714)：
Zhao Yingchao,Liu Pinan,Zhang Na,et al.Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models[J].PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA.2018,115(9):E2077-E2084.doi:10.1073/pnas.1719966115.
APA：
Zhao, Yingchao,Liu, Pinan,Zhang, Na,Chen, Jie,Landegger, Lukas D....&Xu, Lei.(2018).Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,115,(9)
MLA：
Zhao, Yingchao,et al."Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 115..9(2018):E2077-E2084
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