EMT is the dominant program in human colon cancer.

Background: Colon cancer has been classically described by clinicopathologic features that permit the prediction of outcome only after surgical resection and staging.

Methods: We performed an unsupervised analysis of microarray data from 326 colon cancers to identify the first principal component (PC1) of the most variable set of genes. PC1 deciphered two primary, intrinsic molecular subtypes of colon cancer that predicted disease progression and recurrence.

De novo discovery of a gamma-secretase inhibitor response signature using a novel in vivo breast tumor model.

Notch pathway signaling plays a fundamental role in normal biological processes and is frequently deregulated in many cancers. Although several hypotheses regarding cancer subpopulations most likely to respond to therapies targeting the Notch pathway have been proposed, clinical utility of these predictive markers has not been shown. To understand the molecular basis of gamma-secretase inhibitor (GSI) sensitivity in breast cancer, we undertook an unbiased, de novo responder identification study using a novel genetically engineered in vivo breast cancer model.

Inverse relationship between matrix remodeling and lipid metabolism during osteoarthritis progression in the STR/Ort mouse.

Objective: The biologic changes associated with osteoarthritis (OA) are incompletely understood. The aim of this study was to elucidate the molecular mechanisms underlying OA progression in an STR/Ort murine model of spontaneous disease.

Methods: Global patterns of gene expression were assessed using microarray analysis of articular cartilage/subchondral bone from the tibial plateaus of STR/Ort mice at 3, 9, and 12 months of age.

Developing gene expression signatures of pathway deregulation in tumors.

Recent advances in our understanding of cancer biology have led to the development of therapies targeting specific signaling pathways. Molecular targeting promises to improve our ability to predict who will respond by assessing the state of these targeted pathways in patients. However, a single pathway can be deregulated by multiple mechanisms, and for some pathways it may be difficult to assess activation state by analyzing a single oncogene or tumor suppressor.

Using genetic variation to optimize cancer chemotherapy.

The high level of interpatient variation in response to chemotherapy and the lack of objective tools to select chemotherapy regimens for a given tumor type have created a clinical problem. A possible solution may be pharmacogenetics: the study of inherited DNA polymorphisms that influence drug disposition and effects in order to individualize drug treatment. Because unpredictable efficacy and high levels of systemic toxicity are common in cancer chemotherapy, pharmacogenetics is particularly appealing to oncologists.

CEPH individuals are representative of the European American population: implications for pharmacogenetics.

Previous studies have highlighted the use of phenotype generation in immortalized lymphoblastoid cells from the Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees as a powerful means of discovering genes involved in complex biological and pharmacological phenotypes. However, there is no data on how representative CEPH pedigrees are of the general population of European origin for genetic variants of pharmacogenetic significance. A vast amount of data in a population of restricted applicability would be of little value.

Pharmacogenomics: the influence of genomic variation on drug response.

Unpredictable efficacy and toxicity are major hurdles in the administration of many medications. By identifying inherited DNA polymorphisms that influence drug disposition and effects, pharmacogenomics is an exciting tool for the individualization of drug therapies. Single nucleotide polymorphisms (SNP) in genes encoding drug metabolizing enzymes, drug transporters, and DNA repair genes have recently been shown to influence drug toxicity and efficacy.

Genome-wide discovery of loci influencing chemotherapy cytotoxicity.

Little is known about the heritability of chemotherapy activity or the identity of genes that may enable the individualization of cancer chemotherapy. Although numerous genes are likely to influence chemotherapy response, current candidate gene-based pharmacogenetics approaches require a priori knowledge and the selection of a small number of candidate genes for hypothesis testing. In this study, an ex vivo familial genetics strategy using lymphoblastoid cells derived from Centre d'Etude du Polymorphisme Humain reference pedigrees was used to discover genetic determinants of chemotherapy cytotoxicity.

Simple and rapid docetaxel assay in plasma by protein precipitation and high-performance liquid chromatography-tandem mass spectrometry.

A simple, rapid and low cost sample preparation method was developed for quantification of docetaxel in mouse plasma by high-performance liquid chromatography/tandem mass spectrometry with paclitaxel as the internal standard. A small volume of plasma (40 microl) and one-step protein precipitation using methanol and acetonitrile (1:1 (v/v)) were used for sample preparation. The calibration curve for docetaxel in mouse plasma was linear over the range 25-2500 nM.

A mouse-based strategy for cyclophosphamide pharmacogenomic discovery.

Genome-wide mapping approaches are needed to more fully understand the genetic basis of chemotherapy response. Because of technical and ethical limitations, cancer pharmacogenomics has not yet benefited from traditional robust familial genetic strategies. We have therefore explored the use of the inbred mouse as a genetic model system in which to study response to the cytotoxic agent cyclophosphamide.

Cancer pharmacogenomics: current and future applications.

Heterogeneity in patient response to chemotherapy is consistently observed across patient populations. Pharmacogenomics is the study of inherited differences in interindividual drug disposition and effects, with the goal of selecting the optimal drug therapy and dosage for each patient. Pharmacogenomics is especially important for oncology, as severe systemic toxicity and unpredictable efficacy are hallmarks of cancer therapies.

Recent advances in the pharmacogenetics of cancer chemotherapy.

Patient response to chemotherapy varies widely between individuals. Pharmacogenetics is the study of inherited DNA polymorphisms that influence drug disposition and effects, the goal of which is the individualization of drug treatment. As unpredictable efficacy and high levels of systemic toxicity are common in cancer chemotherapy, pharmacogenetics is particularly appealing for oncology.

Using genome-wide mapping in the mouse to identify genes that influence drug response.

Differential drug response is most often likely to be a complex trait, controlled by the combined influences of multiple genes and environmental influences. As a result of theoretical and technical limitations, to date, most clinically useful pharmacogenomic studies in humans have been limited to a small number of candidate genes that have a relatively major impact on drug response. Here, the problems involved in identifying genes that underlie drug response in humans are discussed and the power of mouse genetics as a tool for pharmacogenomic discovery is highlighted.

Murine pharmacogenomics: using the mouse to understand the genetics of drug therapy.

Pharmacogenomics seeks to understand the genetic basis of interindividual differences in drug disposition and effects. Differential drug response is likely to most often be a complex trait, in which multiple genes contribute with varying strengths to the therapeutic phenotype. Due to technical and economic limitations, pharmacogenomic studies in humans are mainly limited to a small number of candidate genes with relatively major influences on drug response.