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Best M.G.,VU University Amsterdam | Sol N.,VU University Amsterdam | In t Veld S.G.J.G.,VU University Amsterdam | Vancura A.,VU University Amsterdam | And 60 more authors.
Cancer Cell | Year: 2017

Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92–0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83–0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources. © 2017 The Authors

Kuiper J.L.,VU University Amsterdam | Heideman D.A.M.,VU University Amsterdam | Wurdinger T.,VU University Amsterdam | Wurdinger T.,Harvard University | And 4 more authors.
Clinical Lung Cancer | Year: 2015

Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown improved progression-free survival (PFS) and overall survival (OS) over chemotherapy in a molecularly defined subgroup of advanced non-small-cell lung cancer (NSCLC) patients (ie, patients with an activating mutation in the EGFR gene). Nevertheless, all EGFR-mutated NSCLC patients develop TKI resistance eventually and there is no registered treatment or therapeutic strategy available for these patients. Several retrospective or small cohort studies have described patients who re-responded to EGFR-TKI treatment after a TKI-free interval ('drug holiday'). To date, no large prospective evaluation of the clinical effects of EGFR-TKI rechallenge in EGFR-mutated NSCLC patients has been performed. Patients and Methods The IRENE (Iressa RE-challenge in advanced, EGFR-mutated NSCLC patients who responded to an EGFR-TKI used as first-line or previous treatment) (Dutch association for pulmonologists [NVALT]-16) trial is a multicenter, open-label, single-arm, single-stage, phase II study to evaluate gefitinib rechallenge in EGFR-mutated NSCLC patients who were previously treated with a TKI followed by a subsequent line of treatment (excluding EGFR-TKIs). The primary objective is disease control rate according to Response Evaluation Criteria in Solid Tumors criteria. Secondary objectives are objective response rate, PFS, OS, mutation characterization of sequential biopsies, VeriStrat correlation to PFS and OS, analysis of tumor-derived RNA in blood platelets and analysis of cell-free DNA in blood plasma. Results The IRENE (NVALT-16) trial will evaluate the safety, efficacy, and feasibility of readministration of gefitinib after an EGFR-TKI-free interval in EGFR-mutated NSCLC patients. Conclusion The study will evaluate gefitinib re-challenge in EGFR-mutated NSCLC patients. The study will also provide more insight into the dynamic development of molecular characteristics of EGFR-mutated NSCLC along the course of the disease. © 2015 Elsevier Inc. All rights reserved.

Best M.G.,VU University Amsterdam | Sol N.,VU University Amsterdam | Kooi I.,VU University Amsterdam | Tannous J.,Harvard University | And 24 more authors.
Cancer Cell | Year: 2015

Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based "liquid biopsies". © 2015 The Authors.

Navis A.C.,Radboud University Nijmegen | van Lith S.A.M.,Radboud University Nijmegen | van Duijnhoven S.M.J.,Radboud University Nijmegen | de Pooter M.,Radboud University Nijmegen | And 14 more authors.
Acta Neuropathologica | Year: 2015

MET has gained interest as a therapeutic target for a number of malignancies because of its involvement in tumorigenesis, invasion and metastasis. At present, a number of inhibitors, both antibodies against MET or its ligand hepatocyte growth factor, and small molecule MET tyrosine kinase inhibitors are in clinical trials. We here describe a novel variant of MET that is expressed in 6 % of high-grade gliomas. Characterization of this mutation in a glioma cell line revealed that it consists of an intronic deletion, resulting in a splice event connecting an intact splice donor site in exon 6 with the next splice acceptor site being that of exon 9. The encoded protein lacks parts of the extracellular IPT domains 1 and 2, encoded by exons 7 and 8, resulting in a novel pseudo-IPT and is named METΔ7−8. METΔ7−8 is located predominantly in the cytosol and is constitutively active. The auto-activating nature of METΔ7−8, in combination with a lack of transmembrane localization, renders METΔ7−8 not targetable using antibodies, although the protein is efficiently deactivated by MET-specific tyrosine kinase inhibitors. Testing of MET-expressing tumors for the presence of this variant may be important for treatment decision making. © 2015, The Author(s).

Best M.G.,VU University Amsterdam | Sol N.,VU University Amsterdam | Zijl S.,VU University Amsterdam | Reijneveld J.C.,VU University Amsterdam | And 5 more authors.
Acta Neuropathologica | Year: 2015

Diffuse gliomas are the most common malignant primary tumors of the central nervous system. Like other neoplasms, these gliomas release molecular information into the circulation. Tumor-derived biomarkers include proteins, nucleic acids, and tumor-derived extracellular vesicles that accumulate in plasma, serum, blood platelets, urine and/or cerebrospinal fluid. Recently, also circulating tumor cells have been identified in the blood of glioma patients. Circulating molecules, vesicles, platelets, and cells may be useful as easily accessible diagnostic, prognostic and/or predictive biomarkers to guide patient management. Thereby, this approach may help to circumvent problems related to tumor heterogeneity and sampling error at the time of diagnosis. Also, liquid biopsies may allow for serial monitoring of treatment responses and of changes in the molecular characteristics of gliomas over time. In this review, we summarize the literature on blood-based biomarkers and their potential value for improving the management of patients with a diffuse glioma. Incorporation of the study of circulating molecular biomarkers in clinical trials is essential for further assessment of the potential of liquid biopsies in this context. © 2015, The Author(s).

thromboDx BV | Entity website

thromboDx acquires a new EUROSTARS grant Posted on November 22, 2015 Amsterdam, The Netherlands thromboDx, the molecular diagnostics company that develops and commercializes blood-based diagnostics through its proprietary platelet-powered technology platform, announces that is has received another EUROSTARS grant. Focusing on the development of companion diagnostics for therapy monitoring of lung cancer patients, thromboDx decided to lead a consortium and submit a proposal under the Read All-in-one cancer diagnostics platform Posted on October 29, 2015 thromboDx collaborators show Blood Platelets offer all-in-one cancer diagnostics platform; study published in Cancer Cell Amsterdam, 29th October 2015: thromboDx, a molecular diagnostic company based in Amsterdam, The Netherlands announced that a 283 subject study shows that its blood platelet based diagnostic platform enables accurate detection, classification and subtyping of cancer in the equivalent Read thromboDx pitching at Falling Walls 2014 Posted on November 6, 2014 Amsterdam thromboDx announces that is has been nominated and elected to be one of the 28 young startup companies pitching at the international Falling Walls conference in Berlin on November 8 and 9 ...

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