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Dingemans A.-M.C.,GROW School for Oncology and Developmental Biology | Mellema W.W.,VU University Amsterdam | Groen H.J.M.,University of Groningen | Van Wijk A.,VU University Amsterdam | And 4 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non-small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib. Experimental Design: In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks. Results: Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0-1.9] but not OS (HR, 1.3; 95% CI, 0.9-1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%). Conclusion: Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy. © 2012 American Association for Cancer Research. Source

Hilgendorf I.,Albert Ludwigs University of Freiburg | Eisele S.,Albert Ludwigs University of Freiburg | Remer I.,Albert Ludwigs University of Freiburg | Schmitz J.,Rigel Pharmaceuticals | And 14 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011

Objective-: Spleen tyrosine kinase (SYK) has come into focus as a potential therapeutic target in chronic inflammatory diseases, such as rheumatoid arthritis and asthma, as well as in B-cell lymphomas. SYK has also been involved in the signaling of immunoreceptors, cytokine receptors, and integrins. We therefore hypothesized that inhibition of SYK attenuates the inflammatory process underlying atherosclerosis and reduces plaque development. Methods and results-: Low-density lipoprotein receptor-deficient mice consuming a high-cholesterol diet supplemented with 2 doses of the orally available SYK inhibitor fostamatinib for 16 weeks showed a dose-dependent reduction in atherosclerotic lesion size by up to 59±6% compared with the respective controls. Lesions of fostamatinib-treated animals contained fewer macrophages but more smooth muscle cells and collagen-characteristics associated with more stable plaques in humans. Mechanistically, fostamatinib attenuated adhesion and migration of inflammatory cells and limited macrophage survival. Furthermore, fostamatinib normalized high-cholesterol diet-induced monocytosis and inflammatory gene expression. Conclusion-: We present the novel finding that the SYK inhibitor fostamatinib attenuates atherogenesis in mice. Our data identify SYK inhibition as a potentially fruitful antiinflammatory therapeutic strategy in atherosclerosis. © 2011 American Heart Association. All rights reserved. Source

Lambregts D.M.J.,MUMC | Beets G.L.,GROW School for Oncology and Developmental Biology | Maas M.,MUMC | Kessels A.G.H.,Maastricht University | And 9 more authors.
Annals of Surgery | Year: 2011

Objective: To prospectively assess the accuracy of gadofosveset-enhanced magnetic resonance imaging (MRI) for nodal staging and restaging in rectal cancer. Background: Accurate preoperative assessment of nodal disease in rectal cancer impacts treatment management. Staging with modern imaging techniques (computed tomography, MRI and endorectal ultrasound) is insufficiently accurate for clinical decision making. This study aims to assess the accuracy of MRI using a novel lymph node magnetic resonance contrast, gadofosveset, for nodal staging and restaging in rectal cancer using a per node comparison with histology as the reference standard. Methods: Sixty-eight patients underwent gadofosveset-enhanced MRI at 1.5T. Twenty-six patients (primary staging group I) were treated with total mesorectal excision (with or without preoperative 5 × 5 Gy) and 42 (restaging group II) underwent a long course of chemoradiation followed by a restaging MRI and resection. Nodes were scored as benign or malignant by 2 radiologists (experienced and junior reader) first on standard MRI, then on gadofosveset-enhanced MRI. For group I the primary staging MRI was compared with histology. In group II the second, restaging MRI was compared with histology. Results:: For the experienced reader, sensitivity, specificity, and area under the ROC-curve (AUC) improved from 76%, 82% and 0.84 on standard MRI to 80%, 97% and 0.96 on gadofosveset-MRI (P < 0.001). For the junior reader results improved from 69%, 85%, and 0.85 on standard MRI to 70%, 95%, and 0.93 on gadofosveset-MRI (P = 0.03). Interobserver agreement was good on both standard MRI (κ 0.73) and gadofosveset-MRI (κ 0.71). Conclusions: This study shows high reproducibility and significantly improved accuracy compared to standard MRI for gadofosveset-enhanced MRI for nodal staging and restaging in rectal cancer. Copyright © 2011 by Lippincott Williams & Wilkins. Source

Delvoux B.,GROW School for Oncology and Developmental Biology | D'Hooghe T.,University Hospital Gasthuisberg | Kyama C.,University Hospital Gasthuisberg | Koskimies P.,Forendo Pharma | And 3 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Endometriosis affects 10%of the women before menopause and has important personal, professional, and societal economic burdens. Because current medical treatments are aimed at reducing the symptoms only, novel therapeutic targets should be identified. Endometriosis is estrogen dependent and in some patients the endometriosis tissue is able to produce estrogens in an autocrine/paracrine manner. In a number of patients, this is the consequence of the high local activity of the 17β-hydroxysteroid-dehydrogenases (17β-HSDs), enzymes able to generate active estrogens from precursors with low activity. Objective: The objective of the study was to identify the 17β-HSD(s) responsible for the high local generation of estrogens in endometriosis and test the possibility to inhibit these enzymes for therapeutic purposes. Design: The expression of different 17β-HSDs involved in the estrogen metabolism was assessed by real-time PCR in eutopic and ectopic tissue from endometriosis patients (n = 14). These biopsies had previously confirmed unbalanced local 17β-HSD activity, which caused high estrogen generation. The possibility to block the synthesis of estrogens by one inhibitor specific for type 1 17β-HSD was assessed by HPLC in tissue lysates from endometriosis tissues (n = 27). Results: In all but one of the patients, a high type 1 17β-HSD level is associated with the unbalanced metabolism of estrogens, leading to higher estrogen synthesis in endometriosis than in the endometrium inside the uterus. Inhibition of type 1 17β-HSD restores to various extents, depending on the patient, the correct metabolism. In 19 of 27 patients analyzed (70%), the 17β-HSD type 1 inhibitor decreased the generation of 17β-estradiol by greater than 85%. Conclusions: Inhibition of 17β-HSD type 1 can be a potential future treatment option aimed at restoring the correct metabolic balance of estrogens in endometriosis patients with increased local 17β-HSD type 1 enzyme activity. (J Clin Endocrinol Metab 99: 276-284, 2014). © Copyright 2014 by The Endocrine Society. Source

Agency: Narcis | Branch: Project | Program: Completed | Phase: Physics, Chemistry and Medicine | Award Amount: | Year: 2007

The overall objective of this study is to expand our theoretical knowledge of the biological effects of the tested drugs in tumors in patients and to identify imaging, tumor cellular and blood characteristics predicting response to the tested agents with or without RT. THE MOST IMPORTANT SPECIFIC RESEARCH QUESTIONS ARE:1) Is the treatment of Rapamycin safe and efficient as an anti-angiogenic agent and as a radiosensitizer when combined with RT in rectal cancer patients ?2) Is the treatment of Nelfinavir safe and efficient as an anti-angiogenic agent and as a radiosensitizer when combined with radiochemotherapy in rectal cancer patients ?3) Are there predictive parameters predicting the response of the tested agents combined with RT ?THE SPECIFIC ASSIGNMENTS TO INVESTIGATE THESE QUESTIONS ARE AS FOLLOWS:1) Determination of the safety of the administration of the drugs during RT using toxicity scores.2) Determination of the tumor cellular response during drug treatment alone and combined with RT using non- invasive imaging, biomarker measurements, and clinical outcome parameters.3) Identification of the changes in molecular and genomic tumor characteristics during drug treatment alone and with RT using repeated imaging, tumor biopsies and blood. BACKGROUND: The clinical outcome of cancer treatment is often limited by the resistance of tumor cells to radio- and chemotherapy. Extensive research in recent years has stimulated the development of promising new targeted drugs against cancer -specific biological pathways in order to overcome this resistance. However, due to the biological heterogeneity of the tumors as well as the specificity of these drugs, not all patients will benefit from the combination of these new compounds with radiotherapy (RT) and/or chemotherapy. Therefore, modern trials testing these combinations need to integrate high quality translational research in order to identify predictors of response. Recent research indicates that tumor responses to RT are most likely determined not only by the tumor cell phenotype, but also by the tumor microenvironment. T his led to the concept of two major lines of current investigations of targeted drugs, first the modulation of the tumor microenvironment, second the targeting of tumor cellular responses itself in order to improve the sensitivity of the tumor to RT. PURPOSE: Preclinical studies from our lab and others have identified the phosphatidol- inositol-3K (PI3K) pathway as an important mediator of tumor cell resistance to RT, thus identifying an attractive target for tumor cell radiosensitization. This stimulated us to propose a translational research clinical project, in which 2 early clinical phase I/II trials will test the safety and activity of two molecular targeted drugs, which have recently emerged as PI3K pathway- targeting agents. Importantly, these drugs, namely Rapamycin (mTor inhibitor) and Nelfinavir (Akt inhibitor) not only target the PI3K pathway, they also function as anti-angiogenic agents, thus ideally fulfilling the promising concept of dual targeting of the tumor microenvironment and the tumor cellular survival pathway. Another important advantage of both drugs is that they are already registered for other indications with a lot of clinical experience and a good safety profile.PLAN: In order to examine the activity of the two targeted drugs in the clinical situation with the integration of high- quality translational research, we chose rectal cancer as a feasible and useful clinical model. We propose two phase I/II phase clinical trials, in which the tested targeted drugs will be added to the standard treatment protocols. Both trials will start as phase I studies in order to first carefully evaluate the acute and postoperative toxicity in a 3+3 cohort dose escalation study. Rapamycin will be administered before and during preoperative short-term RT (5 x 5Gy) in operable rectal cancer. The optimal dose found in phase I will be administered in phase I

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