Integrative Computational Framework, , Links Mutated Driver Genes to Expression Dysregulation Across 19 Cancer Types.

Though somatic mutations play a critical role in driving cancer initiation and progression, the systems-level functional impacts of these mutations-particularly, how they alter expression across the genome and give rise to cancer hallmarks-are not yet well-understood, even for well-studied cancer driver genes. To address this, we designed an integrative machine learning model, Dyscovr, that leverages mutation, gene expression, copy number alteration (CNA), methylation, and clinical data to uncover putative relationships between nonsynonymous mutations in key cancer driver genes and transcriptional changes across the genome. We applied Dyscovr pan-cancer and within 19 individual cancer types, finding both broadly relevant and cancer type-specific links between driver genes and putative targets, including a subset we further identify as exhibiting negative genetic relationships.

Methionine synthase supports tumour tetrahydrofolate pools.

Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). Cobalamin deficiency traps folates as 5-methyl-THF.

IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines.

Insulin-like growth factor receptor 1 (IGF-1R)-targeting therapies are currently at an important crossroad given the low clinical response rates seen in unselected patients. Predictive biomarkers for patient selection are critical for improving clinical benefit. Coupling in vitro sensitivity testing of BMS-754807, a dual IGF-1R/IR inhibitor, with genomic interrogations in 60 human colorectal cancer cell lines, we identified biomarkers correlated with response to BMS-754807.

Cancer cell dependence on unsaturated fatty acids implicates stearoyl-CoA desaturase as a target for cancer therapy.

Emerging literature suggests that metabolic pathways play an important role in the maintenance and progression of human cancers. In particular, recent studies have implicated lipid biosynthesis and desaturation as a requirement for tumor cell survival. In the studies reported here, we aimed to understand whether tumor cells require the activity of either human isoform of stearoyl-CoA-desaturase (SCD1 or SCD5) for survival.

Exome sequencing reveals comprehensive genomic alterations across eight cancer cell lines.

It is well established that genomic alterations play an essential role in oncogenesis, disease progression, and response of tumors to therapeutic intervention. The advances of next-generation sequencing technologies (NGS) provide unprecedented capabilities to scan genomes for changes such as mutations, deletions, and alterations of chromosomal copy number. However, the cost of full-genome sequencing still prevents the routine application of NGS in many areas.

Synergistic antitumor activity of ixabepilone (BMS-247550) plus bevacizumab in multiple in vivo tumor models.

Purpose: Angiogenesis is a critical step in the establishment, growth, and metastasis of solid tumors, and combination of antiangiogenic agents with chemotherapy is an attractive therapeutic option. We investigated the potential of ixabepilone, the first in a new class of antineoplastic agents known as epothilones, to synergize with antiangiogenic agents to inhibit tumor growth.

Experimental Design: In vitro and in vivo cytotoxicity of ixabepilone as single agent and in combination with two targeted antiangiogenic agents, bevacizumab or sunitinib, were examined in preclinical tumor models.