Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

被引:24
|
作者
Mayr, Lisa [1 ,2 ,3 ,4 ]
Guntner, Armin S. [5 ]
Madlener, Sibylle [1 ,2 ,4 ]
Schmook, Maria T. [6 ]
Peyrl, Andreas [1 ,2 ]
Azizi, Amedeo A. [1 ,2 ]
Dieckmann, Karin [7 ]
Reisinger, Dominik [1 ,2 ]
Stepien, Natalia M. [1 ,2 ]
Schramm, Kathrin [8 ,9 ]
Laemmerer, Anna [1 ,2 ,3 ]
Jones, David T. W. [8 ,9 ]
Ecker, Jonas [10 ]
Sahm, Felix [11 ,12 ]
Milde, Till [8 ,10 ]
Pajtler, Kristian W. [8 ,13 ,14 ]
Blattner-Johnson, Mirjam [8 ,9 ]
Strbac, Miroslav [15 ]
Dorfer, Christian [16 ]
Czech, Thomas [16 ]
Kirchhofer, Dominik [1 ,2 ,3 ,4 ]
Gabler, Lisa [3 ,4 ]
Berger, Walter [3 ,4 ]
Haberler, Christine [17 ]
Mullauer, Leonhard [18 ]
Buchberger, Wolfgang [5 ]
Slavc, Irene [1 ,2 ]
Lotsch-Gojo, Daniela [3 ,4 ,16 ]
Gojo, Johannes [1 ,2 ,4 ,8 ,13 ]
机构
[1] Med Univ Vienna, Dept Pediat, A-1090 Vienna, Austria
[2] Med Univ Vienna, Adolescent Med & Comprehens Ctr Pediat, A-1090 Vienna, Austria
[3] Med Univ Vienna, Inst Canc Res, Dept Med 1, A-1090 Vienna, Austria
[4] Med Univ Vienna, Cent Nervous Syst Tumors Unit, Comprehens Canc Ctr, A-1090 Vienna, Austria
[5] Johannes Kepler Univ Linz, Inst Analyt Chem, A-4020 Linz, Austria
[6] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Div Neuroradiol & Musculoskeletal Radiol, A-1090 Vienna, Austria
[7] Med Univ Vienna, Dept Radiotherapy, A-1090 Vienna, Austria
[8] Hopp Childrens Canc Ctr Heidelberg KiTZ, D-69120 Heidelberg, Germany
[9] German Canc Res Ctr, Pediat Glioma Res Grp, D-69120 Heidelberg, Germany
[10] Hopp Childrens Canc Ctr Heidelberg KiTZ, Clin Cooperat Unit Pediat Oncol, D-69120 Heidelberg, Germany
[11] Univ Hosp Heidelberg, Inst Pathol, Dept Neuropathol, D-69120 Heidelberg, Germany
[12] German Canc Res Ctr, German Consortium Translat Canc Res DKTK, Clin Cooperat Unit Neuropathol, D-69120 Heidelberg, Germany
[13] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany
[14] Univ Hosp Heidelberg, Dept Pediat Oncol Hematol & Immunol, D-69120 Heidelberg, Germany
[15] Tree Top Hosp, Dept Lab Med & Pathol, Hulhumale 23000, Maldives
[16] Med Univ Vienna, Dept Neurosurg, A-1090 Vienna, Austria
[17] Med Univ Vienna, Dept Neurol, Div Neuropathol & Neurochem, A-1090 Vienna, Austria
[18] Med Univ Vienna, Dept Pathol, A-1090 Vienna, Austria
来源
JOURNAL OF PERSONALIZED MEDICINE | 2020年 / 10卷 / 04期
基金
奥地利科学基金会;
关键词
NTRK fusion; ROS1; fusion; entrectinib; radiotherapy; CSF penetrance; targeted therapies; trametinib; abemaciclib; ACQUIRED-RESISTANCE; INHIBITOR ENTRECTINIB; CLINICAL-RESPONSE; SOLID TUMORS; CHILDREN; TRK; LAROTRECTINIB; CHEMOTHERAPY; EFFICACY; FUSIONS;
D O I
10.3390/jpm10040290
中图分类号
R19 [保健组织与事业(卫生事业管理)];
学科分类号
摘要
Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.
引用
收藏
页码:1 / 17
页数:17
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