Regulation of eIF4F Translation Initiation Complex by the Peptidyl Prolyl Isomerase FKBP7 in Taxane-resistant Prostate Cancer.

Purpose: Targeted therapies that use the signaling pathways involved in prostate cancer are required to overcome chemoresistance and improve treatment outcomes for men. Molecular chaperones play a key role in the regulation of protein homeostasis and are potential targets for overcoming chemoresistance. We established 4 chemoresistant prostate cancer cell lines and used image-based high-content siRNA functional screening, based on gene-expression signature, to explore mechanisms of chemoresistance and identify new potential targets with potential roles in taxane resistance.

Circulating Tumor Cells with Aberrant Copy Number Predict Progression-Free Survival during Crizotinib Treatment in -Rearranged Non-Small Cell Lung Cancer Patients.

The duration and magnitude of clinical response are unpredictable in -rearranged non-small cell lung cancer (NSCLC) patients treated with crizotinib, although all patients invariably develop resistance. Here, we evaluated whether circulating tumor cells (CTC) with aberrant -FISH patterns [-rearrangement, -copy number gain (-CNG)] monitored on crizotinib could predict progression-free survival (PFS) in a cohort of -rearranged patients. Thirty-nine -rearranged NSCLC patients treated with crizotinib as first ALK inhibitor were recruited prospectively.

Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis.

Background: Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing.

rCGH: a comprehensive array-based genomic profile platform for precision medicine.

Unlabelled: We present rCGH, a comprehensive array-based comparative genomic hybridization analysis workflow, integrating computational improvements and functionalities specifically designed for precision medicine. rCGH supports the major microarray platforms, ensures a full traceability and facilitates profiles interpretation and decision-making through sharable interactive visualizations.

Availability And Implementation: The rCGH R package is available on bioconductor (under Artistic-2.

Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients.

The immunosurveillance mechanisms governing high-risk neuroblastoma (HR-NB), a major pediatric malignancy, have been elusive. We identify a potential role for natural killer (NK) cells, in particular the interaction between the NK receptor NKp30 and its ligand, B7-H6, in the metastatic progression and survival of HR-NB after myeloablative multimodal chemotherapy and stem cell transplantation. NB cells expressing the NKp30 ligand B7-H6 stimulated NK cells in an NKp30-dependent manner.

Chk1 as a new therapeutic target in triple-negative breast cancer.

Objectives: Bioinformatics analyses of pathways and genes differentially expressed between malignant and benign lesions could allow discovering new therapeutic targets. Here, we identified Checkpoint kinase 1 (Chk1) as a potent therapeutic target in triple-negative breast cancer (TNBC).

Materials And Methods: Differential gene expression between TNBC, other malignant and benign lesions was performed on two breast cancer datasets.

Targeting CDC25C, PLK1 and CHEK1 to overcome Docetaxel resistance induced by loss of LZTS1 in prostate cancer.

Docetaxel is used as a standard treatment in patients with metastatic castration-resistant prostate cancer. However, a large subset of patients develops resistance. Understanding resistance mechanisms, which are largely unknown, will allow identification of predictive biomarkers and therapeutic targets.

Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER).

Background: Breast cancer is characterised by genomic alterations. We did a multicentre molecular screening study to identify abnormalities in individual patients with the aim of providing targeted therapy matched to individuals' genomic alterations.

Methods: From June 16, 2011, to July 30, 2012, we recruited patients who had breast cancer with a metastasis accessible for biopsy in 18 centres in France.

Changes in signaling pathways induced by vandetanib in a human medullary thyroid carcinoma model, as analyzed by reverse phase protein array.

Background: Medullary thyroid carcinoma (MTC) is a rare tumor that is caused by activating mutations in the proto-oncogene RET. Vandetanib, a tyrosine-kinase inhibitor, has been recently approved to treat adult patients with metastatic MTC. The aim of this study was to investigate changes in signaling pathways induced by vandetanib treatment in preclinical MTC models, using the reverse-phase protein array method (RPPA).

Mutation of TP53 and alteration of p14(arf) expression in EGFR- and KRAS-mutated lung adenocarcinomas.

Background: In lung adenocarcinoma, inactivation of the tumor suppressor p53 may abrogate a safeguard mechanism preventing the development of tumors with activating mutations in EGFR or KRAS. To assess this hypothesis, we analyzed TP53 mutations and downregulation of p14(arf), a negative regulator of p53 activated by oncogenic signals, in a retrospective series of 96 patients with primary adenocarcinoma of the lung.

Patients And Methods: Mutations in TP53 (exons 4-9), KRAS (exon 1), and EGFR (exons 18-21) were identified by direct sequencing of DNA from formalin-fixed, paraffin-embedded resected tumors.

ERCC1 function in nuclear excision and interstrand crosslink repair pathways is mediated exclusively by the ERCC1-202 isoform.

ERCC1 (excision repair cross-complementation group 1) plays essential roles in the removal of DNA intrastrand crosslinks by nucleotide excision repair, and that of DNA interstrand crosslinks by the Fanconi anemia (FA) pathway and homology-directed repair processes (HDR). The function of ERCC1 thus impacts on the DNA damage response (DDR), particularly in anticancer therapy when DNA damaging agents are employed. ERCC1 expression has been proposed as a predictive biomarker of the response to platinum-based therapy.

Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers.

Background: Molecular segmentation of breast cancer allows identification of small groups of patients who present high sensitivity to targeted agents. A patient, with chemo- and trastuzumab-resistant HER2-overexpressing breast cancer, who presented concomitant acute promyelocytic leukemia, showed a response in her breast lesions to retinoic acid, arsenic, and aracytin. We therefore investigated whether RARA gene amplification could be associated with sensitivity to retinoic acid derivatives in breast cancers.

Changes in signaling pathways induced by vandetanib in a human medullary thyroid carcinoma model, as analyzed by reverse phase protein array.

Background: Medullary thyroid carcinoma (MTC) is a rare tumor that is due to activating mutations in the proto-oncogene RET. Vandetanib, a tyrosine-kinase inhibitor, has been recently approved to treat adult patients with metastatic MTC. The aim of this study was to investigate changes in signaling pathways induced by vandetanib treatment in preclinical MTC models, using the reverse-phase protein array method (RPPA).

Analysis of NKp30/NCR3 isoforms in untreated HIV-1-infected patients from the ANRS SEROCO cohort.

Natural killer (NK) cells play a prominent role at the intersection between innate and cognate immunity, thus influencing the development of multiple pathological conditions including HIV-1-induced AIDS. Not only NK cells directly kill HIV-1-infected cells, but also control the maturation and/or elimination of dendritic cells (DCs). These functions are regulated by the delicate balance between activating and inhibiting receptors expressed at the NK-cell surface.

Impact of bioinformatic procedures in the development and translation of high-throughput molecular classifiers in oncology.

The progressive introduction of high-throughput molecular techniques in the clinic allows for the extensive and systematic exploration of multiple biologic layers of tumors. Molecular profiles and classifiers generated from these assays represent the foundation of what the National Academy describes as the future of "precision medicine". However, the analysis of such complex data requires the implementation of sophisticated bioinformatic and statistical procedures.

19q13-ERCC1 gene copy number increase in non--small-cell lung cancer.

Background: Excision repair cross complementing 1 gene expression level has potential as a prognostic and predictive marker of the efficacy of chemotherapy in NSCLC. The effect of ERCC1 gene copy number (CN) variation (CNV) on ERCC1 expression and the clinical outcome of patients with NSCLC are not known.

Materials And Methods: Copy number variation of the 19q13.

IGF-1R targeting increases the antitumor effects of DNA-damaging agents in SCLC model: an opportunity to increase the efficacy of standard therapy.

Insulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146, and H526 cells in vitro and in vivo.

Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer.

Purpose: Characterization of the genomic changes that drive an individual patient's disease is critical in management of many cancers. In patients with non-small-cell lung cancer (NSCLC), obtaining tumor samples of sufficient size for genomic profiling on recurrence is often challenging. We undertook this study to compare genomic alterations identified in archived primary tumors from patients with NSCLC with those identified in metachronous or synchronous metastases.

Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors.

Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8(+) T cells with a T-helper cell 1 (TH1) profile. Evidence for a natural killer (NK) cell-based control of human malignancies is still largely missing. The KIT tyrosine kinase inhibitor imatinib mesylate markedly prolongs the survival of patients with gastrointestinal stromal tumors (GIST) by direct effects on tumor cells as well as by indirect immunostimulatory effects on T and NK cells.

ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.

Background: The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation.

Methods: We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.

PARP1 impact on DNA repair of platinum adducts: preclinical and clinical read-outs.

Evaluation of DNA repair proteins might provide meaningful information in relation to prognosis and chemotherapy efficacy in Non-Small Cell Lung Cancer (NSCLC) patients. The role of Poly(ADP-Ribose) Polymerase (PARP) in DNA repair of platinum adducts has not been firmly established. We used a DNA repair functional test based on antibody recognition of cisplatin intrastrand platinum adducts on DNA.

Targeting the deregulated spliceosome core machinery in cancer cells triggers mTOR blockade and autophagy.

The spliceosome is a large ribonucleoprotein complex that guides pre-mRNA splicing in eukaryotic cells. Here, we determine whether the spliceosome could constitute an attractive therapeutic target in cancer. Analysis of gene expression arrays from lung, breast, and ovarian cancers datasets revealed that several genes encoding components of the core spliceosome composed of a heteroheptameric Sm complex were overexpressed in malignant disease as compared with benign lesions and could also define a subset of highly aggressive breast cancers.

Prognostic impact of vitamin B6 metabolism in lung cancer.

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis.

Molecular Characteristics of ERCC1-Negative versus ERCC1-Positive Tumors in Resected NSCLC.

Purpose: Excision repair cross-complementation group 1 (ERCC1) is a protein involved in repair of DNA platinum adducts and stalled DNA replication forks. We and others have previously shown the influence of ERCC1 expression upon survival rates and benefit of cisplatin-based chemotherapy in patients with resected non-small-cell lung cancer (NSCLC). However, little is known about the molecular characteristics of ERCC1-positive and ERCC1-negative tumors.

Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors.

The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms.