Dietary fiber content in clinical ketogenic diets modifies the gut microbiome and seizure resistance in mice.

The gut microbiome modulates the anti-seizure effects of the ketogenic diet, but how specific dietary formulations differentially modify the gut microbiome in ways that impact seizure outcome is poorly understood. We find that medical ketogenic infant formulas vary in macronutrient ratio, fat source, and fiber content and differentially promote resistance to 6-Hz seizures in mice. Dietary fiber, rather than fat ratio or source, drives substantial metagenomic shifts in a model human infant microbial community.

Dietary fiber content in clinical ketogenic diets modifies the gut microbiome and seizure resistance in mice.

The gut microbiome is emerging as an important modulator of the anti-seizure effects of the classic ketogenic diet. However, many variations of the ketogenic diet are used clinically to treat refractory epilepsy, and how different dietary formulations differentially modify the gut microbiome in ways that impact seizure outcome is poorly understood. We find that clinically prescribed ketogenic infant formulas vary in macronutrient ratio, fat source, and fiber content and also in their ability to promote resistance to 6-Hz psychomotor seizures in mice.

Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase.

Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors of the catalytic subunit of the PRC2 enhancer of zeste homologue 2 (EZH2) being recently approved for the treatment of epithelioid sarcoma (ES) and follicular lymphoma (FL). Compounds binding to the EED subunit of PRC2 have recently emerged as allosteric inhibitors of PRC2 methyltransferase activity. In contrast to orthosteric inhibitors that target EZH2, small molecules that bind to EED retain their efficacy in EZH2 inhibitor-resistant cell lines.

5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation-Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study.

Purpose: The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized.

Patients And Methods: Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily).

Free energy perturbation in the design of EED ligands as inhibitors of polycomb repressive complex 2 (PRC2) methyltransferase.

Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site.

Extended 5-Year Follow-up Results of a Phase Ib Study (BRIM7) of Vemurafenib and Cobimetinib in -Mutant Melanoma.

Purpose: To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study.

Patients And Methods: This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced -mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naïve ( = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy-progressive disease (PD); = 66]. Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off, 21 days on/7 days off, or continuously.

Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib-treated Patients with -mutated Metastatic Melanoma.

Purpose: Previous investigations identified transcriptional signatures associated with innate resistance to anti-programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for -mutated metastatic melanoma.

Patients And Methods: This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone.

Effects of Molecular Heterogeneity on Survival of Patients With -Mutated Melanoma Treated With Vemurafenib With or Without Cobimetinib in the coBRIM Study.

Purpose: The treatment of advanced -mutated melanomas with BRAF inhibitors (BRAFi) has improved survival, but the efficacy of BRAFi varies among individuals and the development of acquired resistance to BRAFi through reactivation of mitogen-activated protein kinase (MAPK) signaling is common. We performed an exploratory, retrospective analysis to investigate the effects of allelic balance, coexisting oncogene mutations, cell proliferation signaling levels, and loss of PTEN expression on progression-free survival (PFS) in patients in the phase III coBRIM study, which compared the combination of the MEK inhibitor cobimetinib with the BRAFi vemurafenib versus vemurafenib as monotherapy.

Methods: Baseline tumor samples from the intention-to-treat population were analyzed by targeted deep sequencing at a median coverage of 3,600× and by immunohistochemistry for cell proliferation markers, , and PTEN.

Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis.

Background: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy.

Methods: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy.

Informatively clustering longitudinal microarrays using binary or survival outcome data.

The goal of this research is to discover what groups of genes are associated with the disease process. We use binary and failure time outcomes to inform the clustering of longitudinally-collected microarray data. We propose a linear model with normally distributed cluster-specific random effects for the longitudinal gene expression trajectory.

Association of programmed death ligand-1 (PD-L1) expression with treatment outcomes in patients with BRAF mutation-positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib.

The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1 melanoma, with hazard ratios (HRs; PD-L1 vs.

PRMT1-Mediated Translation Regulation Is a Crucial Vulnerability of Cancer.

Through an shRNA screen, we identified the protein arginine methyltransferase Prmt1 as a vulnerable intervention point in murine p53/Rb-null osteosarcomas, the human counterpart of which lacks effective therapeutic options. Depletion of Prmt1 in p53-deficient cells impaired tumor initiation and maintenance and Mechanistic studies reveal that translation-associated pathways were enriched for Prmt1 downstream targets, implicating Prmt1 in translation control. In particular, loss of Prmt1 led to a decrease in arginine methylation of the translation initiation complex, thereby disrupting its assembly and inhibiting translation.

Clinical features of serous retinopathy observed with cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study.

Background: Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF -mutated melanoma treated in the Phase III coBRIM study.

Methods: In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246).

A Phase II Randomized Trial (GO27827) of First-Line FOLFOX Plus Bevacizumab with or Without the MET Inhibitor Onartuzumab in Patients with Metastatic Colorectal Cancer.

Background: Dysregulated hepatocyte growth factor/mesenchymal-epithelial transition (MET) signaling is associated with poor prognosis and resistance to vascular endothelial growth factor inhibition in metastatic colorectal cancer (mCRC). We report outcomes from a double-blind, multicenter phase II trial of the MET inhibitor onartuzumab in combination with mFOLFOX-6 and bevacizumab for mCRC (GO27827; NCT01418222).

Materials And Methods: Patients were randomized 1:1 to receive onartuzumab (10 mg/kg intravenously [IV]) or placebo plus mFOLFOX-6 and bevacizumab (5 mg/kg IV).

Efficacy and Safety of Onartuzumab in Combination With First-Line Bevacizumab- or Pemetrexed-Based Chemotherapy Regimens in Advanced Non-Squamous Non-Small-Cell Lung Cancer.

Background: Onartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non-small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC.

Methods: Patients with untreated stage IIIB/IV non-squamous NSCLC, stratified by MET diagnostic status, were randomized to receive onartuzumab (15 mg/kg intravenously every 3 weeks) or placebo in combination with either paclitaxel/platinum/bevacizumab (bevacizumab cohort), or in combination with platinum/pemetrexed (pemetrexed cohort) with maintenance bevacizumab or pemetrexed and onartuzumab/placebo as appropriate.

Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.

Background: The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies.

Methods: In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily).

Outcome-Driven Cluster Analysis with Application to Microarray Data.

One goal of cluster analysis is to sort characteristics into groups (clusters) so that those in the same group are more highly correlated to each other than they are to those in other groups. An example is the search for groups of genes whose expression of RNA is correlated in a population of patients. These genes would be of greater interest if their common level of RNA expression were additionally predictive of the clinical outcome.

Safety of Onartuzumab in Patients with Solid Tumors: Experience to Date from the Onartuzumab Clinical Trial Program.

Background: Onartuzumab, a recombinant humanized monovalent monoclonal antibody directed against MET, the receptor for the hepatocyte growth factor, has been investigated for the treatment of solid tumors. This publication describes the safety profile of onartuzumab in patients with solid tumors using data from the global onartuzumab clinical development program.

Methods: Adverse event (AE) and laboratory data from onartuzumab phase II/III studies were analyzed and coded into standardized terms according to industry standards.

Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma.

Background: Glioblastoma (GBM) is poorly responsive to current chemotherapy. The nuclear transporter exportin 1 (XPO1, CRM1) is often highly expressed in GBM, which may portend a poor prognosis. Here, we determine the efficacy of novel selective inhibitors of nuclear export (SINE) specific to XPO1 in preclinical models of GBM.

Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific manner.

Recent studies point to a pivotal role of Polycomb repressive complex 2 (PRC2) in stem cell function and cancer. Loss-of-function approaches targeting individual PRC2 subunits have, however, generated findings that are difficult to reconcile. Here, we prevent assembly of both Ezh1- and Ezh2-containing PRC2 complexes by conditional deletion of Eed, a core subunit, and assess hematopoiesis.

Modeling initiation of Ewing sarcoma in human neural crest cells.

Ewing sarcoma family tumors (ESFT) are aggressive bone and soft tissue tumors that express EWS-ETS fusion genes as driver mutations. Although the histogenesis of ESFT is controversial, mesenchymal (MSC) and/or neural crest (NCSC) stem cells have been implicated as cells of origin. For the current study we evaluated the consequences of EWS-FLI1 expression in human embryonic stem cell-derived NCSC (hNCSC).

Ewing tumors that do not overexpress BMI-1 are a distinct molecular subclass with variant biology: a report from the Children's Oncology Group.

Purpose: Ewing sarcoma family tumors (ESFT) are aggressive tumors of putative stem cell origin for which prognostic biomarkers and novel treatments are needed. In several human cancers, high expression of the polycomb protein BMI-1 is associated with poor outcome. We have assessed the potential clinical significance of BMI-1 expression level in ESFT.

B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma.

B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements, also known as "double-hit" lymphomas (DHL), are rare neoplasms characterized by highly aggressive clinical behavior, complex karyotypes, and a spectrum of pathologic features overlapping with Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and B-lymphoblastic lymphoma/leukemia (B-LBL). The clinical and pathologic spectrum of this rare entity, including comparison to other high-grade B-cell neoplasms, has not been well defined. We conducted a retrospective analysis of clinical and pathologic features of 20 cases of DHL seen at our institution during a 5-year period.

Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group.

Purpose: Phase II trials with biochemotherapy (BCT) have shown encouraging response rates in metastatic melanoma, and meta-analyses and one phase III trial have suggested a survival benefit. In an effort to determine the relative efficacy of BCT compared with chemotherapy alone, a phase III trial was performed within the United States Intergroup.

Patients And Methods: Patients were randomly assigned to receive cisplatin, vinblastine, and dacarbazine (CVD) either alone or concurrent with interleukin-2 and interferon alfa-2b (BCT).