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Amsterdam, Netherlands

During the last two decades, an increasing number of microarray studies have identified gene-expression profiles that link disease characteristics to patient outcome. However, despite improvements in technology and the clinical relevance of the identified profiles, only a handful of microarray tests are currently available for clinical use. So why have microarrays, regardless of the great application and success within a research setting, not yet been embraced for routine diagnostic use? Besides the strengths of microarray diagnostics, this perspective will outline the important challenges that need to be considered for successful translation of a gene profile into a routine diagnostic test. Finally, some new microarray technologies will be reviewed and an outlook for the future of diagnostic microarrays will be presented. © 2010 Future Science Ltd. Source

Kress T.R.,University of Wurzburg | Cannell I.G.,University of Leicester | Cannell I.G.,Massachusetts Institute of Technology | Brenkman A.B.,University Utrecht | And 7 more authors.
Molecular Cell | Year: 2011

Expression of the Myc oncoprotein is downregulated in response to stress signals to allow cells to cease proliferation and escape apoptosis, but the mechanisms involved in this process are poorly understood. Cell cycle arrest in response to DNA damage requires downregulation of Myc via a p53-independent signaling pathway. Here we have used siRNA screening of the human kinome to identify MAPKAPK5 (MK5, PRAK) as a negative regulator of Myc expression. MK5 regulates translation of Myc, since it is required for expression of miR-34b and miR-34c that bind to the 3'UTR of MYC. MK5 activates miR-34b/c expression via phosphorylation of FoxO3a, thereby promoting nuclear localization of FoxO3a and enabling it to induce miR-34b/c expression and arrest proliferation. Expression of MK5 in turn is directly activated by Myc, forming a negative feedback loop. MK5 is downregulated in colon carcinomas, arguing that this feedback loop is disrupted during colorectal tumorigenesis. © 2011 Elsevier Inc. Source

Epping M.T.,Netherlands Cancer Institute | Epping M.T.,Beth Israel Deaconess Medical Center | Meijer L.A.T.,University Utrecht | Krijgsman O.,Agendia Inc. | And 4 more authors.
Nature Cell Biology | Year: 2011

We have previously reported a gene expression signature that is a powerful predictor of poor clinical outcome in breast cancer. Among the seventy genes in this expression profile is a gene of unknown function: TSPYL5 (TSPY-like 5, also known as KIAA1750). TSPYL5 is located within a small region at chromosome 8q22 that is frequently amplified in breast cancer, which suggests that TSPYL5 has a causal role in breast oncogenesis. Here, we report that high TSPYL5 expression is an independent marker of poor outcome in breast cancer. Mass spectrometric analysis revealed that TSPYL5 interacts with ubiquitin-specific protease 7 (USP7; also known as herpesvirus-associated ubiquitin-specific protease; HAUSP). USP7 is the deubiquitylase for the p53 tumour suppressor and TSPYL5 reduces the activity of USP7 towards p53, resulting in increased p53 ubiquitylation. We demonstrate that TSPYL5 reduces p53 protein levels and inhibits activation of p53-target genes. Furthermore, expression of TSPYL5 overrides p53-dependent proliferation arrest and oncogene-induced senescence, and contributes to oncogenic transformation in multiple cell-based assays. Our data identify TSPYL5 as a suppressor of p53 function through its interaction with USP7. © 2011 Macmillan Publishers Limited. All rights reserved. Source

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.2.4.1-8 | Award Amount: 7.79M | Year: 2011

Cancer genotyping has identified a number of correlations between mutations in specific genes and responses to targeted anti-cancer drugs, with many mutations occurring in kinases or downstream signaling components. While there are several ongoing large-scale genome re-sequencing studies for the major cancer types, there is no systematic effort to investigate kinase mutations in distinct biological subtypes of these cancers. Here, we will explore the rate of activation of all kinases (the kinome) in two poor-prognosis subtypes of breast cancer for which there are currently no targeted therapies available, namely triple negative (TN) breast tumors lacking the estrogen-, progesterone- and HER2 receptors, constituting 15% of breast cancers, and invasive lobular carcinomas (ILC) of the breast, which represent 10% of breast tumors. Thus, we lack effective targeted therapies for one quarter of all breast cancer patients. In this project, we will identify and validate novel kinase targets for therapy for these TN and ILC subtypes. Kinase targets will be identified via a 4-pronged approach: i) direct re-sequencing of the kinome of 150 TN and 150 ILC tumors, ii) determination of abundance and activation status of kinases in these tumors by reverse phase protein array and tissue microarray technologies, iii) determination of copy number variation by SNP arrays, and iv) mRNA quantitation of the kinome using DNA microarrays. Potential kinase targets for therapy will be validated in preclinical models using RNA interference. Finally, we will perform a phase I/II clinical trial to test the efficacy of a selective PI3K inhibitor in breast cancer. The project will deliver proof-of-concept for novel therapeutic interventions, together with matched molecular diagnostic approaches for patient stratification, for up to 25% of breast cancer patients.

IRVINE, Calif. & AMSTERDAM--(BUSINESS WIRE)--Agendia, a leading molecular diagnostics company that develops and markets genomic diagnostic products, announced at the St. Gallen International Breast Cancer Conference that new guidelines of the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) recommend the MammaPrint® 70-gene breast cancer recurrence assay in Germany’s 2015 guidelines for early-stage invasive breast cancer. "We are extremely pleased that this expert panel has recognized MammaPrint and the substantial body of clinical evidence supporting it," said Jan Egberts, MD, Agendia’s Chief Executive Officer. "MammaPrint is the only breast cancer recurrence assay recommended in the AGO guidelines that is supported by peer-reviewed, prospective five-year outcome data to determine which patients are at low risk of breast cancer recurrence and can therefore safely forego chemotherapy.” At the St. Gallen conference, Agendia sponsored an evening symposia presented by Fatima Cardoso, MD, PhD that highlighted the MINDACT Trial and the U.S. Food & Drug Administration’s (FDA) recent decision to grant MammaPrint its sixth FDA 510(k) clearance. The most recent clearance is for use in formalin-fixed paraffin embedded (FFPE) tissue samples. MammaPrint provides an unambiguous binary Low Risk or High Risk recurrence result. It is part of Agendia’s suite of breast cancer assays that also includes the BluePrint® 80-gene molecular subtyping assay and TargetPrint®, a gene-expression assay. BluePrint provides additional therapy-predictive information, identifying the functional molecular subtype of breast cancer and the associated tumor response to neoadjuvant therapy. Like MammaPrint and TargetPrint, BluePrint is performed on FFPE. It is the most widely available test that uncovers the functional molecular subtype of a woman’s breast cancer. “Agendia’s suite of breast cancer recurrence assays fundamentally changes the conversation at the critical point where treatment decisions are being made,” said Egberts. “While MammaPrint test results eliminate the ambiguity of the intermediate result seen in up to 39% of other tests, functional molecular subtyping by BluePrint provides greater insight into the tumor biology that just isn’t available from most of the other breast cancer recurrence assays on the market.” MammaPrint is available worldwide and has substantial insurance coverage, including Medicare, regional, and national insurers, encompassing an estimated 200 million lives in the U.S. The 14th St. Gallen International Breast Cancer Conference took place in Vienna, Austria, March 18-21, 2015. Agendia is a privately held, leading molecular diagnostics company that develops and markets FFPE-based genomic diagnostic products, which help support physicians with their complex treatment decisions. Agendia’s breast cancer suite was developed using an unbiased gene selection by analyzing the complete human genome. Our offerings include the FDA-cleared MammaPrint FFPE as well as BluePrint, a molecular subtyping assay that provides deeper insight leading to more clinically actionable biology, and TargetPrint®, an ER/PR/HER2 expression assay. MammaPrint is the only breast cancer recurrence assay supported by peer-reviewed, published, prospective outcome data. These tests can help physicians assess a patient’s individual risk for metastasis – that is, which patients are more sensitive to chemo, hormonal, or combination therapy, and which patients may not require these treatments and which patients may be treated with other, less arduous and costly methods. In addition, Agendia has a pipeline of other genomic products in development. The company collaborates with pharmaceutical companies, leading cancer centers and academic groups to develop companion diagnostic tests in the area of oncology. It is also a critical partner in the ISPY-2 and the MINDACT trials. For more information, visit www.agendia.com.

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