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Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

ABSTRACT: Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

SUBMITTER: Guerreiro Stucklin AS

PROVIDER: S-EPMC6761184 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Guerreiro Stucklin Ana S AS Ryall Scott S Fukuoka Kohei K Zapotocky Michal M Lassaletta Alvaro A Li Christopher C Bridge Taylor T Kim Byungjin B Arnoldo Anthony A Kowalski Paul E PE Zhong Yvonne Y Johnson Monique M Li Claire C Ramani Arun K AK Siddaway Robert R Nobre Liana Figueiredo LF de Antonellis Pasqualino P Dunham Christopher C Cheng Sylvia S Boué Daniel R DR Finlay Jonathan L JL Coven Scott L SL de Prada Inmaculada I Perez-Somarriba Marta M Faria Claudia C CC Grotzer Michael A MA Rushing Elisabeth E Sumerauer David D Zamecnik Josef J Krskova Lenka L Garcia Ariza Miguel M Cruz Ofelia O Morales La Madrid Andres A Solano Palma P Terashima Keita K Nakano Yoshiko Y Ichimura Koichi K Nagane Motoo M Sakamoto Hiroaki H Gil-da-Costa Maria Joao MJ Silva Roberto R Johnston Donna L DL Michaud Jean J Wilson Bev B van Landeghem Frank K H FKH Oviedo Angelica A McNeely P Daniel PD Crooks Bruce B Fried Iris I Zhukova Nataliya N Hansford Jordan R JR Nageswararao Amulya A Garzia Livia L Shago Mary M Brudno Michael M Irwin Meredith S MS Bartels Ute U Ramaswamy Vijay V Bouffet Eric E Taylor Michael D MD Tabori Uri U Hawkins Cynthia C

Nature communications 20190925 1

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors aris ...[more]

PMID: 31554817

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Project description:Abstract The STARTRK-NG (Studies of Tumor Alterations Responsive to Targeting Receptor Kinases - Next Generation) trial is a Phase 1/1b study of entrectinib in pediatric patients with cancer, including primary brain tumors, neuroblastoma, and other non-neuroblastoma, extracranial solid tumors harboring NTRK, ROS1, or ALK gene fusions (NCT02650401). Entrectinib is a potent oral, CNS-penetrant, inhibitor of the tyrosine kinases TRKA/B/C (encoded by the genes NTRK1/2/3, respectively), ROS1, and ALK with IC50s < 2?nM (biochemical kinase assay). Overall, gene fusions are rare in the cancer population (<3%); however, they have been seen in over 40 solid tumor histologies, including non-small cell lung cancer, salivary gland cancers, soft tissue sarcomas and glioneuronal tumors. A survey of two pediatric cancer databases, St. Jude pediatric cancer database (PeCan; total n=1,604) and the University of Michigan database (Peds-MiOncoSeq; total n=91), identified malignancies with gene fusions in all three NTRK genes, including infantile fibrosarcoma, juvenile breast cancer, mesoblastic nephroma, intrinsic pontine gliomas, acute leukemias and anaplastic lymphoma. Previously, we reported an objective response rate of 79% was seen in 24 tyrosine kinase inhibitor-naïve patients with solid tumors harboring NTRK, ROS1, or ALK gene fusions, who were treated at doses consistent with the RP2D (Drilon et al, AACR 2016). The most common (>10% incidence) treatment-related adverse events have been fatigue/asthenia, dysgeusia, paresthesia, nausea, myalgia, diarrhea, dizziness, arthralgia, vomiting, and constipation; importantly, there has been no evidence of cumulative toxicity. In addition, we have treated a 20-month-old boy presenting with infantile fibrosarcoma metastatic to the brain, which harbored an ETV6-NTRK3 fusion. Tumor restaging following 1 month of therapy showed a significant tumor regression of CNS metastases accompanied by significant clinical improvement. Together, these data provide compelling evidence to identify pediatric patients harboring NTRK, ROS1, or ALK fusions for enrollment in the STARTRK-NG trial.

Dataset Information

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Publications

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

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