CD200 depletion in glioma enhances antitumor immunity and induces tumor rejection.

Unlabelled: High-grade gliomas are a major health challenge with poor prognosis and high morbidity. Immune-checkpoint inhibitors (ICI) have emerged as promising therapeutic options for several malignancies yet show little efficacy against central nervous system (CNS) tumors. CD200 is a newly recognized immune checkpoint that modulates immune homeostasis.

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors.

Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene . Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST.

Perinatal folate levels do not influence tumor latency or multiplicity in a model of NF1 associated plexiform-like neurofibromas.

Objective: In epidemiological and experimental research, high folic acid intake has been demonstrated to accelerate tumor development among populations with genetic and/or molecular susceptibility to cancer. Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder predisposing affected individuals to tumorigenesis, including benign plexiform neurofibromas; however, understanding of factors associated with tumor risk in NF1 patients is limited. Therefore, we investigated whether pregestational folic acid intake modified plexiform-like peripheral nerve sheath tumor risk in a transgenic NF1 murine model.

Combining nonsense mutation suppression therapy with nonsense-mediated decay inhibition in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) results from germline mutations in the tumor-suppressor gene and predisposes patients to developing nervous system tumors. Twenty percent of NF1 patients harbor nonsense mutations resulting in premature termination codons (PTCs). Nonsense suppression therapies can facilitate ribosomal readthrough of PTCs to restore full-length protein, but their potential in NF1 is underexplored.

Sex differences in methylation profiles are apparent in medulloblastoma, particularly among SHH tumors.

Background: Medulloblastoma, the most common malignant pediatric brain tumor, displays marked sex differences in prevalence of the four main molecular subgroups: SHH, WNT, Group 3 and Group 4. Males are more frequently diagnosed with SHH, Group 3 and 4 tumors, which have worse prognoses than WNT tumors. Little is known about sex differences in methylation profiles within subgroups.

Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric V600-Mutant Low-Grade Glioma.

Purpose: V600 mutations occur in many childhood cancers, including approximately 20% of low-grade gliomas (LGGs). Here, we describe a phase I/II study establishing pediatric dosing and pharmacokinetics of trametinib with or without dabrafenib, as well as efficacy and safety in a disease-specific cohort with V600-mutant LGG; other cohorts will be reported elsewhere.

Methods: This is a four-part, phase I/II study (ClinicalTrials.

MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus.

The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere.

The Role of Socioeconomic Status and Race/Ethnicity in Malignant Peripheral Nerve Sheath Tumor Survival: A Surveillance, Epidemiology, and End Results-Based Analysis.

Background: Recent investigations of malignant peripheral nerve sheath tumor (MPNST) survival have reported higher mortality among non-White individuals. However, previous analyses have not examined the impact of socioeconomic status (SES) on these observations. This study aims to characterize factors associated with cause-specific MPNST survival, including information related to census-tract-level SES (CT-SES).

Young adult males have worse survival than females that is largely independent of treatment received for many types of central nervous system tumors: A National Cancer Database analysis.

Background: Central nervous system (CNS) tumors rank among the top 5 cancers diagnosed in young adults aged 20 to 39 years at diagnosis and show a clear male excess in incidence. It is unknown whether sex differences in survival persist across histologic types and depend on the treatment received.

Methods: From the National Cancer Database (2004-2016), young adults (aged 20-39 years) who had been diagnosed with CNS tumors were identified.

Minority children experience a higher risk of death from many central nervous system tumor types even after accounting for treatment received: A National Cancer Database analysis.

Background: Brain tumors are the leading cause of death from disease in children. Racial/ethnic minority children have poorer outcomes than White children; however, it is not clear whether this association is mediated by treatment received.

Methods: Children (aged 0-19 years) diagnosed with brain tumors in the National Cancer Database (2004-2016) were identified.

Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T cell response in low-grade gliomas.

BACKGROUNDLong-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy.METHODSWe conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs.

Measuring the Effect of Cutaneous Neurofibromas on Quality of Life in Neurofibromatosis Type 1.

Objective: In order to explore the use of Skindex scoring in patients with neurofibromatosis type 1 (NF1) across multiple clinical sites and inform design of additional quality of life measures, we analyzed correlations between Skindex, site, and clinical measures for 79 patients with NF1 from specialized clinics in Sydney, Australia (Royal North Shore Hospital [RNS]) and Minneapolis, Minnesota (University of Minnesota [UMN]).

Methods: The relationship between clinical factors and Skindex scores were explored by clinic site and overall.

Results: A total of 40 participants were recruited from RNS and 39 from UMN.

Selumetinib normalizes Ras/MAPK signaling in clinically relevant neurofibromatosis type 1 minipig tissues in vivo.

Background: The MEK1/2 inhibitor selumetinib was recently approved for neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas, but outcomes could be improved and its pharmacodynamic evaluation in other relevant tissues is limited. The aim of this study was to assess selumetinib tissue pharmacokinetics (PK) and pharmacodynamics (PD) using a minipig model of NF1.

Methods: WT ( = 8) and NF1 ( = 8) minipigs received a single oral dose of 7.

CD200 Immune-Checkpoint Peptide Elicits an Anti-glioma Response Through the DAP10 Signaling Pathway.

Numerous therapies aimed at driving an effective anti-glioma response have been employed over the last decade; nevertheless, survival outcomes for patients remain dismal. This may be due to the expression of immune-checkpoint ligands such as PD-L1 by glioblastoma (GBM) cells which interact with their respective receptors on tumor-infiltrating effector T cells curtailing the activation of anti-GBM CD8 T cell-mediated responses. Therefore, a combinatorial regimen to abolish immunosuppression would provide a powerful therapeutic approach against GBM.

Neurofibromatosis in the Era of Precision Medicine: Development of MEK Inhibitors and Recent Successes with Selumetinib.

Purpose Of Review: Patients with neurofibromatosis type 1 (NF1) are at increased risk for benign and malignant neoplasms. Recently, targeted therapy with the MEK inhibitor class has helped address these needs. We highlight recent successes with selumetinib while acknowledging ongoing challenges for NF1 patients and future directions.

Correction: Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity.

[This corrects the article DOI: 10.18632/oncotarget.1609.