National Center for Tumor Diseases

Heidelberg, Germany

National Center for Tumor Diseases

Heidelberg, Germany
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News Article | May 5, 2017
Site: www.eurekalert.org

Many specialized cells, such as in the skin, gut or blood, have a lifespan of only a few days. Therefore, steady replenishment of these cells is indispensable. They arise from so-called "adult" stem cells that divide continuously. In addition, there is a group of very special stem cells in the bone marrow that were first discovered in 2008 by a research team led by Andreas Trumpp, who is a division head at the DKFZ and director of HI-STEM. These cells remain in a kind of dormancy most of the time and only become active in an emergency such as bacterial or viral infections, heavy blood loss, or in the wake of chemotherapy. Once their work is done, the body sends its most potent stem cells back to sleep. The scientists assume that this protects them from dangerous mutations that may lead to leukemia. The mechanisms that activate these special stem cells or make them go back to sleep after their work is done have remained elusive until now. The scientists have now identified retinoic acid, a vitamin A metabolite, as a crucial factor in this process. If this substance is absent, active stem cells are unable to return to a dormant state and mature into specialized blood cells instead. This means that they are lost as a reservoir. This was shown in studies with specially bred mice whose dormant stem cells are green fluorescent. "If we feed these mice on a vitamin A deficient diet for some time, this leads to a loss of the stem cells," said Nina Cabezas-Wallscheid, who is the first author of the publication. "Thus, we can prove for the first time that vitamin A has a direct impact on blood stem cells." This finding not only enhances our understanding of the development of blood cells, it also sheds new light on prior studies that demonstrate that vitamin A deficiency impairs the immune system. "This shows how vitally important it is to have a sufficient intake of vitamin A from a balanced diet," Cabezas-Wallscheid emphasized. The body cannot produce its own vitamin A. The scientists also have hopes for new prospects in cancer treatment. There is evidence that cancer cells, like healthy stem cells, also rest in a state of dormancy. When dormant, their metabolism is almost completely shut down -- and this makes them resistant to chemotherapy. "Once we understand in detail how vitamin A or retinoic acid, respectively, sends normal and malignant stem cells into dormancy, we can try to turn the tables," explained Trumpp. "If we could make cancer cells temporarily enter an active state, we could thus make them vulnerable to modern therapies." In addition, in collaboration with colleagues from the European Bioinformatics Institute in Cambridge, the team performed genome-wide analyses of single cells and discovered that the transition from dormant to active stem cells and then on to progenitor cells is a continuous one and follows a different path for each individual cell. So far, scientists had assumed that specific cell types develop step by step in a defined pattern. This finding revolutionizes the previous concept of how cell differentiation in the body takes place. The Heidelberg Institute of Stem Cell Research and Experimental Medicine (HI-STEM) is a partnership of the DKFZ and the Dietmar Hopp Foundation. An image for this press release is available at: http://www. Caption: Vitamin A, which is contained in foods like carrots, broccoli and fish, regulates hematopoietic stem cells. Note on use of images related to press releases Use is free of charge. The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) permits one-time use in the context of reporting about the topic covered in the press release. Images have to be cited as follows: "Source: Iris Joval/DKFZ". Distribution of images to third parties is not permitted unless prior consent has been obtained from DKFZ's Press Office (phone: ++49-(0)6221 42 2854, E-mail: presse@dkfz.de). Any commercial use is prohibited. 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.


NOXXON Pharma N.V. (Paris:ALNOX) (Alternext Paris: ALNOX), a biotechnology company whose core focus is on improving cancer treatment by targeting the tumor microenvironment, today announced the signing of an agreement with the National Center for Tumor Diseases (NCT) in Heidelberg under which the NCT will conduct a trial evaluating NOXXON’s lead product candidate NOX-A12 in combination with Keytruda® (pembrolizumab) in metastatic pancreatic and colorectal cancer. In some preclinical studies, NOX-A12 has shown an ability to make the immediate area surrounding a model tumor, the so-called tumor microenvironment, more accessible to the immune system. The ability of many tumors to use the tumor microenvironment to hide from the immune system is believed to contribute to the insensitivity of some tumors towards checkpoint inhibitors, such as Keytruda®. The NCT is a leading center for cancer research and treatment, located in Heidelberg, Germany. It was jointly founded by the German Cancer Research Center (DKFZ), Heidelberg University Hospital, Medical Faculty Heidelberg and German Cancer Aid (Deutsche Krebshilfe) in 2004 to conduct interdisciplinary research for preventing and treating cancer to ultimately benefit patients. The NCT investigators leading the clinical trial include Prof. Dr. Dirk Jäger, Managing Director, head of the clinical and tumor immunology research groups, and Dr. Niels Halama, Group Leader, both recognized leaders in clinical cancer research with significant experience in studying the tumor microenvironment in a clinical setting. Throughout his career, Prof. Dr. Jäger has focused on tumor and immunology as well as the interdisciplinary connections between both fields, both scientifically and clinically. NOXXON’s Chief Medical Officer, Dr. Jarl Ulf Jungnelius, commented: “Dr. Jäger and Dr. Halama are experts in the treatment of metastatic cancer patients as well as the tumor microenvironment. We are extremely pleased that they will be collaborating with NOXXON on this groundbreaking study.” Prof. Dr. Jäger, Managing Director of the NCT Heidelberg, commented: “This trial will enable us to explore the potential of NOX-A12 in combination with Keytruda® to benefit patients with few viable treatment options. Importantly, the trial will help us to better understand the ability of NOX-A12 to modify the tumor microenvironment and make it more accessible to the immune system to facilitate tumor destruction.” NOXXON Pharma N.V. is a clinical-stage biopharmaceutical company focused on cancer treatment. NOXXON’s goal is to significantly enhance the effectiveness of cancer treatments including immuno-oncology approaches (such as immune checkpoint inhibitors) and current standards of care (such as chemotherapy and radiotherapy). NOXXON’s Spiegelmer® platform has generated a proprietary pipeline of clinical-stage product candidates including its lead cancer drug candidate NOX-A12, which is the subject of a clinical immuno-oncology collaboration agreement with Merck & Co. / MSD (NYSE: MRK) to study NOX-A12 combined with Keytruda® (pembrolizumab) in pancreatic and colorectal cancer. NOXXON is supported by a strong group of leading international investors, including TVM Capital, Sofinnova Partners, Edmond de Rothschild Investment Partners, DEWB, NGN and Seventure. NOXXON has its statutory seat in Amsterdam, The Netherlands and its office in Berlin, Germany. Further information can be found at: www.noxxon.com About the National Center for Tumor Diseases (NCT) Heidelberg The NCT Heidelberg is a joint institution of the German Cancer Research Center, Heidelberg University Hospital and German Cancer Aid. The NCT's goal is to link promising approaches from cancer research with patient care from diagnosis to treatment, aftercare and prevention. The interdisciplinary tumor outpatient clinic is the central element of the NCT. Here the patients benefit from an individual treatment plan prepared in a timely manner in interdisciplinary expert rounds, the so-called tumor boards. Participation in clinical studies provides access to innovative therapies. The NCT thereby acts as a pioneering platform that translates novel research results from the laboratory into clinical practice. The NCT cooperates with self-help groups and supports them in their work. Since 2015, a second site for the NCT beside Heidelberg has been under development in Dresden. Certain statements in this communication contain formulations or terms referring to the future or future developments, as well as negations of such formulations or terms, or similar terminology. These are described as forward-looking statements. In addition, all information in this communication regarding planned or future results of business segments, financial indicators, developments of the financial situation or other financial or statistical data contains such forward-looking statements. The company cautions prospective investors not to rely on such forward-looking statements as certain prognoses of actual future events and developments. The company is neither responsible nor liable for updating such information, which only represents the state of affairs on the day of publication.


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.


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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