Dataset Information

Emerging Gene Fusion Drivers in Primary and Metastatic Central Nervous System Malignancies: A Review of Available Evidence for Systemic Targeted Therapies.

ABSTRACT: Primary and metastatic tumors of the central nervous system present a difficult clinical challenge, and they are a common cause of disease progression and death. For most patients, treatment consists primarily of surgery and/or radiotherapy. In recent years, systemic therapies have become available or are under investigation for patients whose tumors are driven by specific genetic alterations, and some of these targeted treatments have been associated with dramatic improvements in extracranial and intracranial disease control and survival. However, the success of other systemic therapies has been hindered by inadequate penetration of the drug into the brain parenchyma. Advances in molecular characterization of oncogenic drivers have led to the identification of new gene fusions driving oncogenesis in some of the most common sources of intracranial tumors. Systemic therapies targeting many of these alterations have been approved recently or are in clinical development, and the ability to penetrate the blood-brain barrier is now widely recognized as an important property of such drugs. We review this rapidly advancing field with a focus on recently uncovered gene fusions and brain-penetrant systemic therapies targeting them. IMPLICATIONS FOR PRACTICE:Driver gene fusions involving receptor tyrosine kinases have been identified across a wide range of tumor types, including primary central nervous system (CNS) tumors and extracranial solid tumors that are associated with high rates of metastasis to the CNS (e.g., lung, breast, melanoma). This review discusses the systemic therapies that target emerging gene fusions, with a focus on brain-penetrant agents that will target the intracranial disease and, where present, also extracranial disease.

SUBMITTER: Brastianos PK

PROVIDER: S-EPMC6192601 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Emerging Gene Fusion Drivers in Primary and Metastatic Central Nervous System Malignancies: A Review of Available Evidence for Systemic Targeted Therapies.

Brastianos Priscilla K PK Ippen Franziska Maria FM Hafeez Umbreen U Gan Hui K HK

The oncologist 20180427 9

Primary and metastatic tumors of the central nervous system present a difficult clinical challenge, and they are a common cause of disease progression and death. For most patients, treatment consists primarily of surgery and/or radiotherapy. In recent years, systemic therapies have become available or are under investigation for patients whose tumors are driven by specific genetic alterations, and some of these targeted treatments have been associated with dramatic improvements in extracranial a ...[more]

PMID: 29703764

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Project description:BackgroundMultiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by both inflammatory demyelination and impaired remyelination. Studies indicate that Toll-like receptor 2 (TLR2) signaling contributes to both the inflammatory component and the defective remyelination in MS. While most MS therapeutics target adaptive immunity, we recently reported that reducing TLR2 signaling in innate immune cells by inducing TLR2 tolerance attenuates adoptively transferred experimental autoimmune encephalomyelitis. Given that previous reports suggest TLR2 signaling also inhibits myelin repair, the objective of this study was to assess how reducing TLR2 signaling through TLR2 tolerance induction affects CNS myelin repair.MethodsChow containing 0.2% cuprizone was fed to male and female wild-type (WT) C57BL/6 mice or TLR2-deficient (TLR2-/-) mice for 5?weeks to induce demyelination. During a 2-week remyelination period following discontinuation of cuprizone, WT mice received either low dose TLR2 ligands to induce systemic TLR2 tolerance or vehicle control (VC). Remyelination was evaluated via electron microscopy and immunohistochemical analysis of microglia and oligodendrocytes in the corpus callosum. Statistical tests included 2-way ANOVA and Mann-Whitney U analyses.ResultsInducing TLR2 tolerance in WT mice during remyelination significantly enhanced myelin recovery, restoring unmyelinated axon frequency and myelin thickness to baseline levels compared to VC-treated mice. Mechanistically, enhanced remyelination in TLR2 tolerized mice was associated with a shift in corpus callosum microglia from a pro-inflammatory iNOS+ phenotype to a non-inflammatory/pro-repair Arg1+ phenotype. This result was confirmed in vitro by inducing TLR2 tolerance in WT microglia cultures. TLR2-/- mice, without TLR2 tolerance induction, also significantly enhanced myelin recovery compared to WT mice, adding confirmation that reduced TLR2 signaling is associated with enhanced remyelination.DiscussionOur results suggest that reducing TLR2 signaling in vivo by inducing TLR2 tolerance significantly enhances myelin repair. Furthermore, the enhanced remyelination resulting from TLR2 tolerance induction is associated with a shift in corpus callosum microglia from a pro-inflammatory iNOS+ phenotype to a non-inflammatory/pro-repair Arg1+ phenotype. While deletion of TLR2 would be an impractical approach in vivo, reducing innate immune signaling through TLR2 tolerance induction may represent a novel, two-pronged approach for treating both inflammatory and myelin repair components of MS.

Dataset Information

Emerging Gene Fusion Drivers in Primary and Metastatic Central Nervous System Malignancies: A Review of Available Evidence for Systemic Targeted Therapies.

Publications

Emerging Gene Fusion Drivers in Primary and Metastatic Central Nervous System Malignancies: A Review of Available Evidence for Systemic Targeted Therapies.

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