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Moldenhauer G.,German Cancer Research Center | Moldenhauer G.,National Center for Tumor Diseases | Salnikov A.V.,German Cancer Research Center | Salnikov A.V.,National Center for Tumor Diseases | And 6 more authors.
Journal of the National Cancer Institute | Year: 2012

Background Human epithelial cell adhesion molecule (EpCAM) is overexpressed in many cancers. Anti-EpCAM antibodies have shown promise in preclinical studies, but showed no tumor regression in a recent phase II clinical trial. Therefore, we generated a novel anti-EpCAM antibody-drug conjugate and assessed whether it showed enhanced antitumor effects. Methods Chemical cross-linking was conducted to covalently conjugate α-amanitin, a toxin known to inhibit DNA transcription, with chiHEA125, a chimerized anti-EpCAM monoclonal antibody, to generate the antibody-drug conjugate α-amanitin-glutarate-chiHEA125 (chiHEA125-Ama). Antiproliferative activity of chiHEA125-Ama was tested in human pancreatic (BxPc-3 and Capan-1), colorectal (Colo205), breast (MCF-7), and bile duct (OZ) cancer cell lines in vitro using [ 3H]-thymidine incorporation assay. Antitumor activity of chiHEA125-Ama was assessed in vivo in immunocompromised mice bearing subcutaneous human BxPc-3 pancreatic carcinoma xenograft tumors (n = 66 mice). Cell proliferation and apoptosis were evaluated in xenograft tumors by immunohistochemistry. All statistical tests were two-sided. Results In all cell lines, chiHEA125-Ama reduced cell proliferation (mean half maximal inhibitory concentration [IC50] = 2.5 × 10 -10 to 5.4 × 10 -12 M). A single dose of chiHEA125-Ama inhibited BxPc-3 xenograft tumor growth (chiHEA125 [control, n = 4 mice] vs chiHEA125-Ama [n = 6 mice], dose of 15 mg/kg with respect to IgG and 50 μg/kg with respect to α-amanitin, mean relative increase in tumor volume on day 16 = 884% vs-79%, difference = 963%, 95% CI = 582% to 1344%, P = .019). Two higher doses of chiHEA125-Ama (100 μg/kg with respect to α-amanitin), administered 1 week apart (n = 10 mice per group), led to complete tumor regression in nine of 10 (90%) mice compared with chiHEA125, during the observation period of 16 days; increased apoptosis and reduced cell proliferation were observed in mice treated with chiHEA125-Ama. Conclusion This preclinical study suggests that anti-EpCAM antibody conjugates with α-amanitin have the potential to be highly effective therapeutic agents for pancreatic carcinomas and various EpCAM-expressing malignancies. © 2012 The Author.


Dimopoulos M.A.,National and Kapodistrian University of Athens | Terpos E.,National and Kapodistrian University of Athens | Goldschmidt H.,Universitatsklinikum | Goldschmidt H.,National Center for Tumor Diseases | And 3 more authors.
Cancer Treatment Reviews | Year: 2012

Renal impairment (RI) is a common complication affecting patients with multiple myeloma (MM). Timely identification of MM-related RI and early treatment with novel antimyeloma agents can reverse renal damage in a high proportion of patients and improve outcomes. The IMiDs® immunomodulatory compound lenalidomide (Len) in combination with dexamethasone (Dex) is an effective and well-tolerated regimen for patients with relapsed or refractory (RR) MM. A retrospective analysis of Phase III data has shown that Len/Dex remains effective and well-tolerated in patients with moderate or severe RI, albeit with an increase in myelosuppression. This analysis demonstrated that in a high proportion of patients Len/Dex treatment can reverse MM-related RI and restore normal function. Lenalidomide has a predominantly renal route of excretion and in patients with RI the plasma concentration and half-life of the drug are significantly increased. As a consequence, lower starting doses are required in patients with RI to avoid over-exposure and an increased risk of adverse events, while maintaining good therapeutic index. A prospective cohort study in 50 patients with RRMM has reported that when Len/Dex dosing was adjusted according to renal function, response rates and survival outcomes were similar in patients with and without RI, and there was no increase in adverse events in patients with RI. Further clinical studies are required to confirm the efficacy and tolerability of Len/Dex regimens in MM patients with RI, and to evaluate the impact of reversing renal damage in terms of patient survival. © 2012 Elsevier Ltd.


Strasser B.,University Institute of Health Sciences | Steindorf K.,German Cancer Research Center | Steindorf K.,National Center for Tumor Diseases | Wiskemann J.,National Center for Tumor Diseases | And 6 more authors.
Medicine and Science in Sports and Exercise | Year: 2013

PURPOSE: Current evidence suggests many health benefits from physical activity during and after cancer treatment. However, the optimal exercise program for cancer survivors has not yet been established. The purpose of this meta-analysis was to summarize evidence for the efficacy of resistance training (RT) interventions to improve muscle strength and body composition among adult cancer survivors. We also investigate potential dose-response relationships between intensity, duration, and frequency of RT and assessed outcomes. METHODS: A systematic literature review of the Clinical Trial Register, Cochrane Trial Register, MEDLINE, and EMBASE literature databases was undertaken. Studies were included if they were randomized controlled trials (RCT) comparing RT with an exercise or nonexercise control group in cancer survivors during and after treatment. Thirteen articles from 11 RCT met our inclusion criteria. We performed a random-effects meta-analysis to determine weighted mean differences (WMD) with 95% confidence intervals using the Cochrane Review Manager 5.0.25. A random-effects metaregression model was performed to examine dose-response relationships between RT variables and assessed outcomes. RESULTS: Quantitative evidence shows a large effect of RT on lower-limb and upper-limb muscle strength (WMD: +14.57 kg, P = 0.0005 and +6.90 kg, P < 0.00001, respectively) and moderate effects on lean body mass and percentage of body fat (WMD: +1.07 kg, P < 0.0001 and -2.08%, P = 0.003, respectively). A small positive effect of RT was noted on Functional Assessment of Cancer Therapy-Fatigue (P = 0.05). Upper-limb muscle strength and percentage of body fat improved to a greater extent when RT interventions were of low to moderate intensity (≤75% one-repetition maximum, P = 0.042). CONCLUSIONS: RT was shown to be associated with clinically important positive effects on muscular function and body composition in patients during treatment or in long-term follow-up. Copyright © 2013 by the American College of Sports Medicine.


Endris V.,University of Heidelberg | Penzel R.,University of Heidelberg | Warth A.,University of Heidelberg | Muckenhuber A.,University of Heidelberg | And 4 more authors.
Journal of Molecular Diagnostics | Year: 2013

In the context of personalized oncology, screening for somatic tumor mutations is crucial for prediction of an individual patient's response to therapy. Massive parallel sequencing (MPS) has been suggested for routine diagnostics, but this technology has not been sufficiently evaluated with respect to feasibility, reliability, and cost effectiveness with routine diagnostic formalin-fixed, paraffin-embedded material. We performed ultradeep targeted semiconductor-based MPS (190 amplicons covering hotspot mutations in 46 genes) in a variety of formalin-fixed, paraffin-embedded diagnostic samples of lung adenocarcinoma tissue with known EGFR mutations (n = 28). The samples reflected the typical spectrum of tissue material for diagnostics, including small biopsies and samples with low tumor-cell content. Using MPS, we successfully sequenced all samples, with a mean read depth of 2947 reads per amplicon. High-quality sequence reads were obtained from samples containing ≥10% tumor material. In all but one sample, variant calling identified the same EGFR mutations as were detected by conventional Sanger sequencing. Moreover, we identified 43 additional mutations in 17 genes and detected amplifications in the EGFR and ERBB2 genes. MPS performance was reliable and independent of the type of material, as well as of the fixation and extraction methods, but was influenced by tumor-cell content and the degree of DNA degradation. Using sample multiplexing, focused MPS approached diagnostically acceptable cost rates. Copyright © 2013 American Society for Investigative Pathology.


Warth A.,University of Heidelberg | Muley T.,Translational Research Unit | Kossakowski C.A.,University of Heidelberg | Goeppert B.,University of Heidelberg | And 4 more authors.
American Journal of Surgical Pathology | Year: 2015

Tumor spread, in general, is the most important factor determining outcome in almost all malignant tumors. Lung tumors are unique with respect to potential routes for tumor dissemination, as apart from vascular, nodal, and distant spread of tumor cells, tumor spread through air spaces (STAS) might also occur. However, morphologic criteria for STAS and its prognostic impact have not been defined yet. We evaluated a series of 569 resected pulmonary adenocarcinomas (ADCs) for predefined morphologic criteria of limited and extensive STAS and correlated our findings with clinical, morphologic, molecular, and outcome data. Limited (21.6%) or extensive (29%) STAS was present in roughly half of all ADCs. The presence and type of STAS was tightly linked to specific growth patterns (P<0.001). STAS was much more prevalent in high-stage (P<0.001), nodal-positive (P<0.001) ADC with distant metastasis (P=0.010). STAS was associated with lower rates of EGFR (P=0.009) but higher rates of BRAF (P=0.016) mutations. Furthermore, STAS was associated with significantly reduced overall (P=0.020) and disease-free survival (P=0.004), which was growth pattern but not stage independent. We analyzed morphologic characteristics of a yet underestimated type of tumor spread of pulmonary ADC through air spaces. STAS is a novel morphologic prognosticator, which should be further validated and considered for implementation in routine diagnostic evaluation and reporting. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


News Article | February 15, 2017
Site: www.eurekalert.org

After an infection with the Epstein-Barr virus (EBV), the virus persists in the body throughout a person's lifetime, usually without causing any symptoms. About one third of infected teenagers and young adults nevertheless develop infectious mononucleosis, also known as glandular fever or kissing disease, which usually wears off after a few weeks. In rare cases, however, the virus causes cancer, particularly lymphomas and cancers of the stomach and of the nasopharynx. Scientists have been trying for a long time to elucidate how the viruses reprogram cells into becoming cancer cells. "The contribution of the viral infection to cancer development in patients with a weakened immune system is well understood" says Henri-Jacques Delecluse, a cancer researcher at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg. "But in the majority of cases, it remains unclear how an EBV infection leads to cancer development." In their present publication, Delecluse, in collaboration with Ingrid Hoffmann, also from the DKFZ, and their respective groups present a new and surprising explanation for this phenomenon. The scientists have shown for the first time that a protein component of the virus itself promotes the development of cancer. When a dividing cell comes in contact with Epstein-Barr viruses, a viral protein present in the infectious particle called BNRF1 frequently leads to the formation of an excessive number of spindle poles (centrosomes). As a result, the chromosomes are no longer divided equally and accurately between the two daughter cells -- a known and acknowledged cancer risk factor. By contrast, Epstein-Barr viruses that had been made deficient of BNRF1 did not interfere with chromosome distribution to the daughter cells. EBV, a member of the herpes virus family, infects B cells of the immune system. The viruses normally remain silent in a few infected cells, but occasionally they reactivate to produce viral offspring that infects nearby cells. As a consequence, these cells come in close contact with the harmful viral protein BNRF1, thus having a greater risk of transforming into cancer cells. "The novelty of our work is that we have uncovered a component of the viral particle as a cancer driver," Delecluse said. "All human tumors viruses that have been studied so far cause cancer in a completely different manner. Usually, the genetic material of the viruses needs to be permanently present in the infected cell, thus causing the activation of one or several viral genes that cause cancer development. However, these gene products are not present in the infectious particle itself". Delecluse and his colleagues therefore suspect that EBV could cause the development of additional tumors. These tumors might have previously not been linked to the virus because they do not carry the viral genetic material. For Delecluse, the consequence that follows from his findings is immediate: "We must push forward with the development of a vaccine against EBV infection. This would be the most direct strategy to prevent an infection with the virus. Our latest results show that the first infection could already be a cancer risk and this fits with earlier work that showed an increase in the incidence of Hodgkin's lymphoma in people who underwent an episode of infectious mononucleosis." Experts estimate that an EBV vaccine could prevent two percent of all cancer cases worldwide. Delecluse and his group already developed a vaccine prototype in 2005. It is based on so-called 'virus-like particles', or VLPs. These are empty virus shells that mimic an EBV infectious particle, thus prompting the body to mount an immune response. Henri-Jacques Delecluse is a medical researcher and, since 2012, he has been director of a research unit (Unité Inserm 1074) that was established at the DKFZ by the French 'Institut National de la Santé et de la Recherche Médicale' (Inserm). In addition, the DKFZ is a member of the German Center for Infection Research (DZIF), one of six German Centers for Health Research that the German government has established with the goal of fighting major common diseases. The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.


Schmidt M.E.,German Cancer Research Center | Chang-Claude J.,German Cancer Research Center | Vrieling A.,German Cancer Research Center | Heinz J.,University of Hamburg | And 3 more authors.
Journal of Cancer Survivorship | Year: 2012

Introduction: Fatigue is a frequent problem during and after cancer treatment. We investigated different courses of fatigue from pre-diagnosis, through therapy, to long-term survivorship and evaluated potential implications on long-term quality of life (QoL). Methods: Breast cancer patients diagnosed in 2001-2005 were recruited in a case-control study in Germany (MARIE). At follow-up in 2009 (median 5. 8 years, MARIEplus), patients self-reported current fatigue and QoL status using validated questionnaires (FAQ, EORTC QLQ-C30). In addition, survivors retrospectively rated fatigue levels pre-diagnosis, during different treatment phases, and 1 year post-surgery. Our analyses included 1,928 disease-free cancer survivors and comparisons with fatigue and QoL scores from the general population. Results: Fatigue levels were substantially increased during chemotherapy and radiotherapy. Among patients who received both therapies, 61. 4% reported higher, 30. 0% same, and 8. 6% lower fatigue levels during chemotherapy compared to radiotherapy. Courses of fatigue varied widely between individuals. Survivors with persisting long-term fatigue had significantly and markedly worse scores for all QoL functions and symptoms about 6 years post-diagnosis than other survivors and compared to the general population. Survivors without substantial fatigue post-treatment had QoL scores largely comparable to the general population. Discussions/conclusion: Chemotherapy appears to have a stronger impact on fatigue than radiotherapy. Breast cancer survivors may experience long-term QoL comparable to the general population, even when suffering from substantial fatigue during treatment. Yet, persistent fatigue post-treatment may lead to extensive long-term loss in QoL concerning physical, social, cognitive, and financial aspects. Implications for cancer survivors: Fatigue management should be obligatory during and post cancer treatment. © 2011 Springer Science+Business Media, LLC.


Winkler E.C.,National Center for Tumor Diseases | Wiemann S.,German Cancer Research Center
Expert Review of Molecular Diagnostics | Year: 2016

Introduction: Improvements in sequencing technologies have helped to refine diagnosis and patient stratification via molecular genetic testing for a number of conditions. Consequently, sequencing has increasingly entered clinical routine. Reduced cost, combined with enhanced throughput has helped to place sequencing also in the commercial market thus moving beyond particular indications. Diverse kinds of sequencing approaches are applied, ranging from gene panel to whole-genome sequencing. All these have proven successful in the identification of causal and therapeutically relevant alterations to the benefit of patients. However, a number of technical and ethical issues induce challenges that require their appreciation, societal discussion and consensual decision. Areas covered: In the following paper, advantages and disadvantages of different DNA sequencing strategies towards their application within and outside a clinical context are discussed particularly in the light of the incidence and impact genetic findings have at the personal as well as societal level. Expert commentary: We regard the comprehensive education of citizens about these challenges a prerequisite to reach a societal consensus on the exploitation of the huge opportunities while not neglecting the potential and real dangers that are associated with the resulting data. © 2016 Informa UK Limited, trading as Taylor & Francis Group


Gupta I.,Genome Biology Unit | Clauder-Munster S.,Genome Biology Unit | Klaus B.,Center for Statistical Data Analysis | Jarvelin A.I.,Genome Biology Unit | And 8 more authors.
Molecular Systems Biology | Year: 2014

Recent research has uncovered extensive variability in the boundaries of transcript isoforms, yet the functional consequences of this variation remain largely unexplored. Here, we systematically discriminate between the molecular phenotypes of overlapping coding and non-coding transcriptional events from each genic locus using a novel genome-wide, nucleotide-resolution technique to quantify the half-lives of 3′ transcript isoforms in yeast. Our results reveal widespread differences in stability among isoforms for hundreds of genes in a single condition, and that variation of even a single nucleotide in the 3′ untranslated region (UTR) can affect transcript stability. While previous instances of negative associations between 3′ UTR length and transcript stability have been reported, here, we find that shorter isoforms are not necessarily more stable. We demonstrate the role of RNA-protein interactions in conditioning isoform-specific stability, showing that PUF3 binds and destabilizes specific polyadenylation isoforms. Our findings indicate that although the functional elements of a gene are encoded in DNA sequence, the selective incorporation of these elements into RNA through transcript boundary variation allows a single gene to have diverse functional consequences. © 2014 The Authors.


Gabriel R.,National Center for Tumor Diseases | Lombardo A.,Vita-Salute San Raffaele University | Arens A.,National Center for Tumor Diseases | Miller J.C.,Sangamo BioSciences | And 12 more authors.
Nature Biotechnology | Year: 2011

Zinc-finger nucleases (ZFNs) allow gene editing in live cells by inducing a targeted DNA double-strand break (DSB) at a specific genomic locus. However, strategies for characterizing the genome-wide specificity of ZFNs remain limited. We show that nonhomologous end-joining captures integrase-defective lentiviral vectors at DSBs, tagging these transient events. Genome-wide integration site analysis mapped the actual in vivo cleavage activity of four ZFN pairs targeting CCR5 or IL2RG. Ranking loci with repeatedly detectable nuclease activity by deep-sequencing allowed us to monitor the degree of ZFN specificity in vivo at these positions. Cleavage required binding of ZFNs in specific spatial arrangements on DNA bearing high homology to the intended target site and only tolerated mismatches at individual positions of the ZFN binding sites. Whereas the consensus binding sequence derived in vivo closely matched that obtained in biochemical experiments, the ranking of in vivo cleavage sites could not be predicted in silico. Comprehensive mapping of ZFN activity in vivo will facilitate the broad application of these reagents in translational research. © 2011 Nature America, Inc. All rights reserved.

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