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Berlin Brandenburg

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  • Brain Neoplasms
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  • 1
    Language: English
    In: The Journal of clinical investigation, April 2011, Vol.121(4), pp.1344-8
    Description: Pilocytic astrocytoma (PA) is the most common type of primary brain tumor in children and the second most frequent cancer in childhood. Children with incompletely resected PA represent a clinically challenging patient cohort for whom conventional adjuvant therapies are only moderately effective. This has produced high clinical demand for testing of new molecularly targeted treatments. However, the development of new therapeutics for PA has been hampered by the lack of an adequate in vivo tumor model. Recent studies have identified activation of MAPK signaling, mainly by oncogenic BRAF activation, as a hallmark genetic event in the pathogenesis of human PA. Using in vivo retroviral somatic gene transfer into mouse neural progenitor cells, we have shown here that ectopic expression of the activated BRAF kinase domain is sufficient to induce PA in mice. Further in vitro analyses demonstrated that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with the kinase inhibitor sorafenib. Our in vivo model for PA shows that the activated BRAF kinase domain is sufficient to induce PA and highlights its role as a potential therapeutic target.
    Keywords: Astrocytoma -- Etiology ; Brain Neoplasms -- Etiology ; Proto-Oncogene Proteins B-Raf -- Genetics
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 2
    Language: English
    In: CNS oncology, July 2013, Vol.2(4), pp.359-76
    Description: Histone deacetylase inhibitors (HDACis) have fascinated researchers in almost all fields of oncology for many years owing to their pleiotropic effects on nearly every aspect of cancer biology. Since the approval of the first HDACi vorinostat for the treatment of cutaneous T-cell leukemia in 2006, more than a hundred clinical trials have been initiated with a HDACi as a single agent or in combination therapy. Although a number of epigenetic and nonepigenetic molecular mechanisms of action have been proposed, biomarkers for response prediction and patient selection are still lacking. One of the inherent problems in the field of HDACis is their 'reverse' history of drug development: these compounds reached clinical application at an early stage, before the biology of their targets, HDAC1-11, was sufficiently understood. This review summarizes the current knowledge on the human family of HDACs as drug targets in pediatric and adult brain tumors, the efficacy and molecular action of HDACis in preclinical models, as well as the current status of the clinical development of these compounds in the field of neuro-oncology.
    Keywords: Brain Neoplasms -- Drug Therapy ; Histone Deacetylase Inhibitors -- Therapeutic Use ; Histone Deacetylases -- Metabolism
    ISSN: 20450907
    E-ISSN: 2045-0915
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  • 3
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 June 2010, Vol.16(12), pp.3240-52
    Description: Medulloblastomas are the most common malignant brain tumors in childhood. Survivors suffer from high morbidity because of therapy-related side effects. Thus, therapies targeting tumors in a specific manner with small molecules such as histone deacetylase (HDAC) inhibitors are urgently warranted. This study investigated the expression levels of individual human HDAC family members in primary medulloblastoma samples, their potential as risk stratification markers, and their roles in tumor cell growth. Gene expression arrays were used to screen for HDAC1 through HDAC11. Using quantitative real time reverse transcriptase-PCR and immunohistochemistry, we studied the expression of HDAC5 and HDAC9 in primary medulloblastoma samples. In addition, we conducted functional studies using siRNA-mediated knockdown of HDAC5 and HDAC9 in medulloblastoma cells. HDAC5 and HDAC9 showed the highest expression in prognostically poor subgroups. This finding was validated in an independent set of medulloblastoma samples. High HDAC5 and HDAC9 expression was significantly associated with poor overall survival, with high HDAC5 and HDAC9 expression posing an independent risk factor. Immunohistochemistry revealed a strong expression of HDAC5 and HDAC9 proteins in most of all primary medulloblastomas investigated. siRNA-mediated knockdown of HDAC5 or HDAC9 in medulloblastoma cells resulted in decreased cell growth and cell viability. HDAC5 and HDAC9 are significantly upregulated in high-risk medulloblastoma in comparison with low-risk medulloblastoma, and their expression is associated with poor survival. Thus, HDAC5 and HDAC9 may be valuable markers for risk stratification. Because our functional studies point toward a role in medulloblastoma cell growth, HDAC5 and HDAC9 may potentially be novel drug targets.
    Keywords: Biomarkers, Tumor -- Metabolism ; Brain Neoplasms -- Metabolism ; Histone Deacetylases -- Metabolism ; Medulloblastoma -- Metabolism ; Repressor Proteins -- Metabolism
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 4
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 July 2011, Vol.17(14), pp.4650-60
    Description: Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS) through activation of the mitogen-activated protein kinase (MAPK) pathway. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas (PA), the most prevalent brain neoplasm in children. We investigated whether OIS is induced in PA. We tested expression of established senescence markers in three independent cohorts of sporadic PA. We also assessed for OIS in vitro, using forced expression of wild-type and V600E-mutant BRAF in two astrocytic cell lines: human telomerase reverse transcriptase (hTERT)-immortalized astrocytes and fetal astrocytes. Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic β-galactosidase activity, low KI-67 index, and induction of p16(INK4a) but not p53 in the majority of 52 PA samples (46 of 52; 88.5%). Overexpression of a number of senescence-associated genes [CDKN2A (p16), CDKN1A (p21), CEBPB, GADD45A, and IGFBP7] was shown at the mRNA level in two independent PA tumor series. In vitro, sustained activation of wild-type or mutant BRAF induced OIS in both astrocytic cell lines. Loss of p16(INK4a) in immortalized astrocytes abrogated OIS, indicative of the role of this pathway in mediating this phenomenon in astrocytes. OIS is a mechanism of tumor suppression that restricts the progression of benign tumors. We show that it is triggered in PAs through p16(INK4a) pathway induction following aberrant MAPK activation. OIS may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas, and the high overall survival of affected patients.
    Keywords: Astrocytoma -- Genetics ; Brain Neoplasms -- Genetics ; MAP Kinase Signaling System -- Genetics ; Oncogene Proteins -- Metabolism
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 5
    In: Pediatric Blood & Cancer, March 2018, Vol.65(3), pp.n/a-n/a
    Description: Infants with low‐grade glioma (LGG) and diencephalic syndrome have a poor outcome. The patient described here had a desmoplastic infantile astrocytoma harboring a BRAF V600E mutation. After relapse following initial standard chemotherapy treatment, he was successfully treated with the BRAF V600E inhibitor vemurafenib at the age of 3 years 11 months and 5 years 0 months. A rapid response was observed on both occasions. This illustrates the possibility of continuous oncogenic addiction and the therapeutic potential of BRAF V600E inhibitor monotherapy in LGG, even in very young severely compromised children. BRAF V600E inhibition in LGG and possible (re‐)treatment regimens are briefly discussed.
    Keywords: Braf V600e Inhibitor ; Child ; Desmoplastic Infantile Astrocytoma ; Infant ; Low‐Grade Glioma ; Vemurafenib
    ISSN: 1545-5009
    E-ISSN: 1545-5017
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  • 6
    Language: English
    In: Cell, 20 January 2012, Vol.148(1-2), pp.59-71
    Description: Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer. ► Complex chromosomal alterations (chromothripsis) observed in medulloblastomas ► Cancers with such alterations harbor TP53 mutations ► Context-specific link between the status of p53 and likelihood of chromothripsis ► p53 status and chromothripsis also correlate with aggressive acute myeloid leukemia Connecting p53 status and chromothripsis in specific types of cancer provides a genetic basis for the more aggressive forms of medulloblastoma and leukemia.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 7
    In: Brain Pathology, November 2012, Vol.22(6), pp.848-860
    Description: Ependymomas are primary brain tumors found throughout the central nervous system (CNS) in children and adults. Currently, many treatment protocols stratify grade I and II ependymomas as low‐risk tumors, whereas grade III anaplastic ependymomas are considered high‐risk tumors. The prognostic significance of World Health Organization (WHO) grade II or III, however, remains debated, and it is furthermore increasingly recognized that the pathologic differentiation between grades II and III is arbitrary in daily practice, thus resulting in imprecise risk stratification. Therefore, prognostic markers enabling more precise stratification to guide treatment decisions are urgently needed. An analysis of n = 379 tumor samples revealed that protein expression of nestin, a marker for neural stem and progenitor cells established as a routine staining in most neuropathology centers, is associated with poor outcome in intracranial ependymomas. Most importantly, nestin‐positive grade II ependymomas have the same prognosis as grade III ependymomas. Multivariable analysis demonstrates that nestin positivity is an independent marker for poor progression‐free survival (PFS) and overall survival (OS). Gene expression analysis for transcriptionally co‐regulated genes revealed a strong association of developmental and epigenetic processes with nestin. In summary, our data implicate nestin as a useful novel marker for intracranial ependymoma risk stratification easily implementable in routine diagnostics.
    Keywords: Ependymoma ; Nestin ; Risk Stratification ; Who Grade
    ISSN: 1015-6305
    E-ISSN: 1750-3639
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  • 8
    Language: English
    In: Nature medicine, 2016, Vol.22(11), pp.1314-1320
    Description: Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in similar to 10% of cases. These MET fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion-expressing glioblastoma with the targeted inhibitor crizotinib. This therapy led to substantial tumor shrinkage and associated relief of symptoms, but new treatment-resistant lesions appeared, indicating that combination therapies are likely necessary to achieve a durable clinical response
    Keywords: Medicine ; Biology;
    ISSN: 1078-8956
    ISSN: 1546-170x
    E-ISSN: 1546170X
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  • 9
    Language: English
    In: Radiation Oncology, 01 October 2012, Vol.7(1), p.170
    Description: Abstract Background To report on establishment of workflow and clinical results of particle therapy at the Heidelberg Ion Therapy Center. Materials and methods We treated 36 pediatric patients (aged 21 or younger) with particle therapy at HIT. Median age was 12 years (range 2-21 years), five patients (14%) were younger than 5 years of age. Indications included pilocytic astrocytoma, parameningeal and orbital rhabdomyosarcoma, skull base and cervical chordoma, osteosarcoma and adenoid-cystic carcinoma (ACC), as well as one patient with an angiofibroma of the nasopharynx. For the treatment of small children, an anesthesia unit at HIT was established in cooperation with the Department of Anesthesiology. Results Treatment concepts depended on tumor type, staging, age of the patient, as well as availability of specific study protocols. In all patients, particle radiotherapy was well tolerated and no interruptions due to toxicity had to be undertaken. During follow-up, only mild toxicites were observed. Only one patient died of tumor progression: Carbon ion radiotherapy was performed as an individual treatment approach in a child with a skull base recurrence of the previously irradiated rhabdomyosarcoma. Besides this patient, tumor recurrence was observed in two additional patients. Conclusion Clinical protocols have been generated to evaluate the real potential of particle therapy, also with respect to carbon ions in distinct pediatric patient populations. The strong cooperation between the pediatric department and the department of radiation oncology enable an interdisciplinary treatment and stream-lined workflow and acceptance of the treatment for the patients and their parents.
    Keywords: Proton Radiation ; Carbon Ion Radiotherapy ; Children ; Medicine
    ISSN: 1748-717X
    E-ISSN: 1748-717X
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  • 10
    Language: English
    In: Oncotarget, 26 July 2016, Vol.7(30), pp.47918-47926
    Description: Pilocytic astrocytoma and ganglioglioma may occur in inaccessible or surgically difficult areas. In case of incomplete resection, the availability of biological predictors of tumour progression could be particularly important. To this end, an analysis of p53 codon 72 polymorphism and assessment of its role as prognostic marker were performed.The status of the p53 Arg72Pro polymorphism was evaluated by pyrosequencing method in a multicenter cohort of 170 paediatric patients. Genotype/phenotype associations were investigated either by means of bivariate or multivariate analyses.In the partially resected pilocytic astrocytomas, the Arg/Arg variant predicts early tumour progression (median survival time: 23.1 months) and is associated with poor event-free survival (p value = 0.0009). This finding remains true also in case of adjuvant therapies, with a 5-year event-free survival of 30.6% for cases with Arg/Arg variant vs. 78.7% for those with other genotypes. There is no association between ganglioglioma and the polymorphism.The assessment of Arg/Arg variant could improve the management of pilocytic astrocytoma. TP53 codon 72 analysis could distinguish low-risk cases, in which surgery could be conservative, from high-risk cases needing an aggressive surgery plan.
    Keywords: Tp53 ; Low-Grade Gliomas ; Paediatric ; Pilocytic Astrocytoma ; Polymorphism ; Astrocytoma -- Genetics ; Brain Neoplasms -- Genetics ; Tumor Suppressor Protein P53 -- Genetics
    E-ISSN: 1949-2553
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