Gliomas, a genetically heterogeneous group of primary central nervous system tumors, continue to pose a significant clinical challenge. Discovery of chromosomal rearrangements involving kinase genes has enabled precision therapy, and improved outcomes in several malignancies. Positing that similar benefit could be accomplished for patients with brain cancer, we evaluated The Cancer Genome Atlas (TCGA) glioblastoma dataset. Functional validation of the oncogenic potential and inhibitory sensitivity of discovered ROS1 fusions was performed using three independent cell-based model systems, and an murine xenograft study. analysis revealed previously unreported intrachromosomal 6q22 microdeletions that generate-fusions from TCGA glioblastoma dataset. fusions in primary glioma and ependymoma were independently corroborated from MSK-IMPACT and Foundation Medicine clinical datasets. GOPC-ROS1 is a recurrent ROS1 fusion in primary central nervous system (CNS) tumors. CEP85L-ROS1 and GOPC-ROS1 are transforming oncogenes in cells of astrocytic lineage, and amenable to pharmacologic inhibition with several ROS1 inhibitors even when occurring concurrently with other cancer hotspot aberrations frequently associated with glioblastoma. Oral monotherapy with a brain-permeable ROS1 inhibitor, lorlatinib, significantly prolonged survival in an intracranially xenografted tumor model generated from a ROS1 fusion-positive glioblastoma cell line. Our findings highlight that CNS tumors should be specifically interrogated for these rare intrachromosomal 6q22 microdeletion events that generate actionable ROS1 fusions. ROS1 fusions in primary brain cancer may be amenable for clinical intervention with kinase inhibitors, and this holds the potential of novel treatment paradigms in these treatment-refractory cancer types, particularly in glioblastoma.

◥Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor.Significance: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.

wrote the manuscript, which was revised and approved by all authors. COMPETING INTERESTSSanford Burnham Prebys Medical Discovery Institute has filed a patent application with R.J.W.-R., A.G. and C.F.W. listed as inventors. PCT application serial number PCT/US2018/048916 was filed on August 30, 2018, and is currently pending. This application covers the potential of p53 as a biomarker for responsiveness to T cell based immunotherapy, and the use of TNF receptor superfamily ligands to increase MHC expression and enhance immunotherapy.

Embryonal tumors (ET) of the central nervous system (CNS) in children encompass a wide clinical spectrum of aggressive malignancies. Until recently, the overlapping morphological features of these lesions posed a diagnostic challenge and undermined discovery of optimal treatment strategies. However, with the advances in genomic technology and the outpouring of biological data over the last decade, clear insights into the molecular heterogeneity of these tumors are now well delineated. The major subtypes of ETs of the CNS in children include medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and embryonal tumors with multilayered rosettes (ETMR), which are now biologically and clinically characterized as different entities. These important developments have paved the way for treatments guided by risk stratification as well as novel targeted therapies in efforts to improve survival and reduce treatment burden.

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