Time is critical for definitive treatment, especially for advanced malignancy patients, and the entire process of implantation and propagation followed by drug testing typically takes 12C16 weeks

Time is critical for definitive treatment, especially for advanced malignancy patients, and the entire process of implantation and propagation followed by drug testing typically takes 12C16 weeks. predict response to cetuximab in patients with colorectal malignancy using OncoFinder pathway activation strength (PAS), based on the transcriptomic data of the tumors. We first evaluated our OncoFinder pathway activation strength model in a set of transcriptomic data obtained from patient-derived xenograft (PDx) models established from colorectal malignancy biopsies. Then, the approach and models were validated using a clinical trial data set. PAS could efficiently predict patients response to cetuximab, and thus holds promise as a selection criterion for cetuximab treatment in metastatic colorectal malignancy. Introduction Colorectal malignancy (CRC) is the third most commonly diagnosed malignancy in the United States. The American Malignancy Society estimates that, in 2015, 132?700 people will be diagnosed with CRC and that 49? 700 people will pass away from the disease. Distant metastasis is the main Cyclizine 2HCl cause of death in CRC patients, and 40C50% of newly diagnosed patients are already in advanced stages when diagnosed.1 In the past decade, the management of patients with metastatic CRC (mCRC) has been profoundly improved by the introduction of anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies, cetuximab (mutation status is a strong predictive factor for anti-EGFR therapy in patients with mCRC. Although anti-EGFR therapy has little or no effect in colorectal tumors harboring Kmutations (codons 12 and 13 in the exon 2), patients with wild-type Ktumors are more likely to benefit from the treatment.6,7 However, Kwild-type status is not a reliable predictor of tumor response to anti-EGFR monoclonal antibodies, as only about 40C60% of patients with wild-type Kbenefit from anti-EGFR therapy.6,7 EGFR orchestrates various processes involved in cell growth, differentiation, survival, cell cycle progression, angiogenesis and drug sensitivity via Ras-Raf-MAPK, PI3K-AKT, JAK/STAT and other pathways.8 Therefore, accumulative evidence suggests that an increase in the EGFR gene copy number and dysregulation of downstream EGFR signaling pathway modulators, such as BRAF, HRAS, NRAS, PI3K and AKT/PTEN, are also important factors when determining tumor sensitivity to EGFR antibodies.9,10 Previous studies have exhibited that neither EGFR activation nor EGFR expression level itself is capable of discriminating responses to cetuximab in CRC.11C13 Moreover, EGFR mutations are rare in CRC and have no clinical relevance with regard to the activity of anti-EGFR therapy.14,15 Although multiple efforts have been made to identify additional biomarkers to predict cetuximab response in wild-type KCRC,7,16C19 no reliable markers of clinical utility have been identified. Therefore, there is an urgent need to develop new strategies to identify patients whose tumors could respond to and clinically Cyclizine 2HCl benefit from anti-EGFR therapy in mCRC. We hypothesized that analysis of the comprehensive tumor pathway activation profile may be a more efficient strategy to segregate cetuximab responders from non-responders in the Kwild-type populace than previously explained methods, such as evaluating the gene expression profile,16 Mouse monoclonal to MSX1 selective pathways expression status19 or genotyping EGFR downstream effectors for activating mutations.18 As a novel approach to improving the decision-making in the treatment of solid cancers, we propose a new drug screening and efficacy prediction tool, OncoFinder, for both quantitative and qualitative analysis of the intracellular signaling pathway activation.20,21 OncoFinder performs pathway-level analysis of an expression data set of tumors and determines the pathway activation strength (PAS). PAS is usually a measurement of the cumulative value of perturbations of a signaling pathway and serves as a valuable malignancy biomarker.20C22 In the current study, this approach was extensively evaluated for the prediction of cetuximab sensitivity using the expression microarray data set from patient-derived CRC tumorgrafts and validated in a cohort of CRC patient Cyclizine 2HCl data available from a Phase II exploratory clinical trial. TumorGrafts or patient-derived xenografts are established from directly implanted tumor tissue samples into an immunodeficient mouse. TumorGrafts are progressively recognized as representative clinical models and are vastly superior to commonly used cell collection xenografts.23C26 TumorGraft or patient-derived xenograft models maintain global gene expression patterns, DNA copy-number alterations, mutational status, metastatic potential, clinical predictability and tumor architecture of the parental primary tumors.25,27 Therefore, personalized tumorgrafts can be successfully used as model platforms for drug testing and improving decision-making in tumor treatment. Time is critical for definitive treatment, especially for advanced malignancy patients, and the entire process of implantation and propagation followed by drug testing typically takes 12C16.