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Article ; Online: Prognostic Cancer Gene Expression Signatures

Yuquan Qian / Jimmy Daza / Timo Itzel / Johannes Betge / Tianzuo Zhan / Frederik Marmé / Andreas Teufel

Cells, Vol 10, Iss 648, p

Current Status and Challenges

2021 Volume 648

Abstract: Current staging systems of cancer are mainly based on the anatomical extent of disease. They need refinement by biological parameters to improve stratification of patients for tumor therapy or surveillance strategies. Thanks to developments in genomic, ... ...

Abstract	Current staging systems of cancer are mainly based on the anatomical extent of disease. They need refinement by biological parameters to improve stratification of patients for tumor therapy or surveillance strategies. Thanks to developments in genomic, transcriptomic, and big-data technologies, we are now able to explore molecular characteristics of tumors in detail and determine their clinical relevance. This has led to numerous prognostic and predictive gene expression signatures that have the potential to establish a classification of tumor subgroups by biological determinants. However, only a few gene signatures have reached the stage of clinical implementation so far. In this review article, we summarize the current status, and present and future challenges of prognostic gene signatures in three relevant cancer entities: breast cancer, colorectal cancer, and hepatocellular carcinoma.
Keywords	prognostic ; gene expression signature ; breast cancer ; hepatocellular carcinoma ; colorectal cancer ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Patient-Derived Organoids of Cholangiocarcinoma

Christopher Fabian Maier / Lei Zhu / Lahiri Kanth Nanduri / Daniel Kühn / Susan Kochall / May-Linn Thepkaysone / Doreen William / Konrad Grützmann / Barbara Klink / Johannes Betge / Jürgen Weitz / Nuh N. Rahbari / Christoph Reißfelder / Sebastian Schölch

International Journal of Molecular Sciences, Vol 22, Iss 8675, p

2021 Volume 8675

Abstract: Cholangiocarcinoma (CC) is an aggressive malignancy with an inferior prognosis due to limited systemic treatment options. As preclinical models such as CC cell lines are extremely rare, this manuscript reports a protocol of cholangiocarcinoma patient- ... ...

Abstract	Cholangiocarcinoma (CC) is an aggressive malignancy with an inferior prognosis due to limited systemic treatment options. As preclinical models such as CC cell lines are extremely rare, this manuscript reports a protocol of cholangiocarcinoma patient-derived organoid culture as well as a protocol for the transition of 3D organoid lines to 2D cell lines. Tissue samples of non-cancer bile duct and cholangiocarcinoma were obtained during surgical resection. Organoid lines were generated following a standardized protocol. 2D cell lines were generated from established organoid lines following a novel protocol. Subcutaneous and orthotopic patient-derived xenografts were generated from CC organoid lines, histologically examined, and treated using standard CC protocols. Therapeutic responses of organoids and 2D cell lines were examined using standard CC agents. Next-generation exome and RNA sequencing was performed on primary tumors and CC organoid lines. Patient-derived organoids closely recapitulated the original features of the primary tumors on multiple levels. Treatment experiments demonstrated that patient-derived organoids of cholangiocarcinoma and organoid-derived xenografts can be used for the evaluation of novel treatments and may therefore be used in personalized oncology approaches. In summary, this study establishes cholangiocarcinoma organoids and organoid-derived cell lines, thus expanding translational research resources of cholangiocarcinoma.
Keywords	cholangiocarcinoma ; translational surgical oncology ; organoids ; patient-derived organoids ; xenograft model ; orthotopic xenograft ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The drug-induced phenotypic landscape of colorectal cancer organoids

Johannes Betge / Niklas Rindtorff / Jan Sauer / Benedikt Rauscher / Clara Dingert / Haristi Gaitantzi / Frank Herweck / Kauthar Srour-Mhanna / Thilo Miersch / Erica Valentini / Kim E. Boonekamp / Veronika Hauber / Tobias Gutting / Larissa Frank / Sebastian Belle / Timo Gaiser / Inga Buchholz / Ralf Jesenofsky / Nicolai Härtel /

Tianzuo Zhan / Bernd Fischer / Katja Breitkopf-Heinlein / Elke Burgermeister / Matthias P. Ebert / Michael Boutros

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 15

Abstract: The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes ... ...

Abstract	The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.
Keywords	Science ; Q
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A multicenter open-label phase II trial to evaluate nivolumab and ipilimumab for 2nd line therapy in elderly patients with advanced esophageal squamous cell cancer (RAMONA)

Nadja M. Meindl-Beinker / Johannes Betge / Tobias Gutting / Elke Burgermeister / Sebastian Belle / Tianzuo Zhan / Nadine Schulte / Martin Maenz / Matthias P. Ebert / Nicolai Haertel

BMC Cancer, Vol 19, Iss 1, Pp 1-

2019 Volume 8

Abstract: Abstract Background Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients. The impact of 2nd line chemotherapy is poorly defined. Recent data demonstrated effectiveness of checkpoint inhibitors in different squamous ... ...

Abstract	Abstract Background Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients. The impact of 2nd line chemotherapy is poorly defined. Recent data demonstrated effectiveness of checkpoint inhibitors in different squamous cell carcinomas. Therefore, we assess combined nivolumab/ipilimumab as 2nd line therapy in elderly ESCC patients. Methods RAMONA is a multicenter open-label phase II trial. The primary objective is to demonstrate a significant survival benefit of nivolumab/ipilimumab in advanced ESCC compared to historical data of standard chemotherapy. Primary endpoint is therefore overall survival (OS). Major secondary objective is the evaluation of tolerability. Time to QoL deterioration will thus be determined as key secondary endpoint. Further secondary endpoints are tumor response, PFS and safety. We aim to recruit a total of n = 75 subjects that have to be > 65 years old. Eligibility is determined by the geriatric status (G8 screening and Deficit Accumulation Frailty Index (DAFI)). A safety assessment will be performed after a 3 cycle run-in phase of nivolumab (240 mg Q2W) to justify escalation for eligible patients to combined nivolumab (240 mg Q2W) and ipilimumab (1 mg/kg Q6W), while the other patients will remain on nivolumab only. RAMONA also includes translational research sub-studies to identify predictive biomarkers, including PD-1 and PD-L1 evaluation at different time points, establishment of organoid cultures and microbiome analyses for response prediction. Discussion The RAMONA trial aims to implement checkpoint inhibitors for elderly patients with advanced ESCC as second line therapy. Novel biomarkers for checkpoint-inhibitor response are analyzed in extensive translational sub-studies. Trial registration EudraCT Number: 2017–002056-86; NCT03416244, registered: 31.1.2018.
Keywords	Esophageal squamous cell cancer ; Elderly ; Comprehensive geriatric assessment ; Checkpoint inhibitors ; Personalized medicine ; Geriatric oncology ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Subject code	610 ; 616
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Second-line therapy with nivolumab plus ipilimumab for older patients with oesophageal squamous cell cancer (RAMONA)

Matthias P Ebert, ProfMD / Nadja M Meindl-Beinker, PhD / Tobias Gutting, MD / Martin Maenz, PhD / Johannes Betge, MD / Nadine Schulte, MD / Tianzuo Zhan, MD / Philip Weidner, MD / Elke Burgermeister, PhD / Ralf Hofheinz, ProfMD / Arndt Vogel, ProfMD / Stefan Angermeier, MD / Claus Bolling, MD / Maike de Wit, ProfMD / Ralf Jakobs, ProfMD / Meinolf Karthaus, ProfMD / Gertraud Stocker, MD / Peter Thuss-Patience, MD / Tobias Leidig, PhD /

Timo Gaiser, ProfMD / Jakob N Kather, ProfMD / Nicolai Haertel, MD

The Lancet. Healthy Longevity, Vol 3, Iss 6, Pp e417-e

a multicentre, open-label phase 2 trial

2022 Volume 427

Abstract: Summary: Background: The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. ...

Abstract	Summary: Background: The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. We assessed the safety and efficacy of combined nivolumab and ipilimumab therapy in this population. Methods: This multicentre, open-label, phase 2 trial done in 32 sites in Germany included patients aged 65 years and older with oesophageal squamous cell carcinoma and disease progression or recurrence following first-line therapy. Patients were treated with nivolumab (240 mg fixed dose once every 2 weeks, intravenously) in the safety run-in phase and continued with nivolumab and ipilimumab (nivolumab 240 mg fixed dose once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks, intravenously). The primary endpoint was overall survival, which was compared with a historical cohort receiving standard chemotherapy in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03416244. Findings: Between March 2, 2018, and Aug 20, 2020, we screened 75 patients with advanced oesophageal squamous cell carcinoma. We enrolled 66 patients (50 [76%] men and 16 [24%] women; median age 70·5 years [IQR 67·0–76·0]), 44 (67%) of whom received combined nivolumab and ipilimumab therapy and 22 (33%) received nivolumab alone. Median overall survival time at the prespecified data cutoff was 7·2 months (95% CI 5·7–12·4) and significantly higher than in a historical cohort receiving standard chemotherapy (p=0·0063). The most common treatment-related adverse events were fatigue (12 [29%] of 42), nausea (11 [26%]), and diarrhoea (ten [24%]). Grade 3–5 treatment-related adverse events occurred in 13 (20%) of 66 patients. Treatment-related death occurred in one patient with bronchiolitis obliterans while on nivolumab and ipilimumab treatment. Interpretation: Patients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from ...
Keywords	Geriatrics ; RC952-954.6 ; Medicine ; R
Subject code	616 ; 610
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer

Tianzuo Zhan / Giulia Ambrosi / Anna Maxi Wandmacher / Benedikt Rauscher / Johannes Betge / Niklas Rindtorff / Ragna S. Häussler / Isabel Hinsenkamp / Leonhard Bamberg / Bernd Hessling / Karin Müller-Decker / Gerrit Erdmann / Elke Burgermeister / Matthias P. Ebert / Michael Boutros

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 17

Abstract: Wnt signaling is necessary for colorectal cancer tumorigenesis and stem cell maintenance. Here, the authors identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling and show that clinically approved MEK inhibitors inadvertently induce ... ...

Abstract	Wnt signaling is necessary for colorectal cancer tumorigenesis and stem cell maintenance. Here, the authors identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling and show that clinically approved MEK inhibitors inadvertently induce stem cell plasticity in colorectal cancer
Keywords	Science ; Q
Language	English
Publishing date	2019-05-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 17

Abstract	Wnt signaling is necessary for colorectal cancer tumorigenesis and stem cell maintenance. Here, the authors identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling and show that clinically approved MEK inhibitors inadvertently induce stem cell plasticity in colorectal cancer
Keywords	Science ; Q
Language	English
Publishing date	2019-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor AResearch in context

Elke Burgermeister / Francesca Battaglin / Fagr Eladly / Wen Wu / Frank Herweck / Nadine Schulte / Johannes Betge / Nicolai Härtel / Jakob N. Kather / Cleo-Aron Weis / Timo Gaiser / Alexander Marx / Christel Weiss / Ralf Hofheinz / Ian S. Miller / Fotios Loupakis / Heinz-Josef Lenz / Annette T. Byrne / Matthias P. Ebert

EBioMedicine, Vol 45, Iss , Pp 139-

2019 Volume 154

Abstract: Background: The identification of new biomarkers and the development of novel, targetable contexts of vulnerability are of urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor-Nuclear-Translocator-Like ( ... ...

Abstract	Background: The identification of new biomarkers and the development of novel, targetable contexts of vulnerability are of urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor-Nuclear-Translocator-Like (ARNTL/BMAL1) is a circadian clock-regulated transcription factor promoting expression of genes involved in angiogenesis and tumour progression. We hypothesised that BMAL1 increases expression of the vascular endothelial growth factor A VEGFA gene and, thereby, confers resistance to anti-angiogenic therapy with bevacizumab (Beva), a clinically used antibody for neutralization of VEGFA. Methods: PCR and immunohistochemistry were employed to assess BMAL1 expression in mice (C57BL/6 J Apcmin/+; BALB/c nu/nu xenografts) and CRC patients under combination chemotherapy with Beva. BMAL1 single nucleotide gene polymorphisms (SNPs) were analysed by DNA-microarray in clinical samples. BMAL1 functions were studied in human CRC cell lines using colorimetric growth, DNA-binding and reporter assays. Findings: In murine CRCs, high BMAL1 expression correlated with poor preclinical response to Beva treatment. In CRC patients' tumours (n = 74), high BMAL1 expression was associated with clinical non-response to combination chemotherapy with Beva (p = .0061) and reduced progression-free survival (PFS) [p = .0223, Hazard Ratio (HR) = 1.69]. BMAL1 SNPs also correlated with shorter PFS (rs7396943, rs7938307, rs2279287) and overall survival (OS) [rs11022780, *p = .014, HR = 1.61]. Mechanistically, Nuclear-Receptor-Subfamily-1-Group-D-Member-1 (NR1D1/REVERBA) bound a − 672 bp Retinoic-Acid-Receptor-Related-Orphan-Receptor-Alpha-responsive-element (RORE) adjacent to a BMAL1 DNA-binding motif (E-box) in the VEGFA gene promoter, resulting in increased VEGFA synthesis and proliferation of human CRC cell lines. Interpretation: BMAL1 was associated with Beva resistance in CRC. Inhibition of REVERBA-BMAL1 signalling may prevent resistance to anti-angiogenic therapy. Fund: This work was in part supported by the European Commission Seventh Framework Programme (Contract No. 278981 [ANGIOPREDICT]). Keywords: BMAL1, ARNTL, REVERBA, Bevacizumab, Colorectal cancer, VEGFA
Keywords	Medicine ; R ; Medicine (General) ; R5-920
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Amplicon sequencing of colorectal cancer

Johannes Betge / Grainne Kerr / Thilo Miersch / Svenja Leible / Gerrit Erdmann / Christian L Galata / Tianzuo Zhan / Timo Gaiser / Stefan Post / Matthias P Ebert / Karoline Horisberger / Michael Boutros

PLoS ONE, Vol 10, Iss 5, p e

variant calling in frozen and formalin-fixed samples.

2015 Volume 0127146

Abstract: Next generation sequencing (NGS) is an emerging technology becoming relevant for genotyping of clinical samples. Here, we assessed the stability of amplicon sequencing from formalin-fixed paraffin-embedded (FFPE) and paired frozen samples from colorectal ...

Abstract	Next generation sequencing (NGS) is an emerging technology becoming relevant for genotyping of clinical samples. Here, we assessed the stability of amplicon sequencing from formalin-fixed paraffin-embedded (FFPE) and paired frozen samples from colorectal cancer metastases with different analysis pipelines. 212 amplicon regions in 48 cancer related genes were sequenced with Illumina MiSeq using DNA isolated from resection specimens from 17 patients with colorectal cancer liver metastases. From ten of these patients, paired fresh frozen and routinely processed FFPE tissue was available for comparative study. Sample quality of FFPE tissues was determined by the amount of amplifiable DNA using qPCR, sequencing libraries were evaluated using Bioanalyzer. Three bioinformatic pipelines were compared for analysis of amplicon sequencing data. Selected hot spot mutations were reviewed using Sanger sequencing. In the sequenced samples from 16 patients, 29 non-synonymous coding mutations were identified in eleven genes. Most frequent were mutations in TP53 (10), APC (7), PIK3CA (3) and KRAS (2). A high concordance of FFPE and paired frozen tissue samples was observed in ten matched samples, revealing 21 identical mutation calls and only two mutations differing. Comparison of these results with two other commonly used variant calling tools, however, showed high discrepancies. Hence, amplicon sequencing can potentially be used to identify hot spot mutations in colorectal cancer metastases in frozen and FFPE tissue. However, remarkable differences exist among results of different variant calling tools, which are not only related to DNA sample quality. Our study highlights the need for standardization and benchmarking of variant calling pipelines, which will be required for translational and clinical applications.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy

Dominiek Smeets / Ian S. Miller / Darran P. O’Connor / Sudipto Das / Bruce Moran / Bram Boeckx / Timo Gaiser / Johannes Betge / Ana Barat / Rut Klinger / Nicole C. T. van Grieken / Chiara Cremolini / Hans Prenen / Massimiliano Mazzone / Jeroen Depreeuw / Orna Bacon / Bozena Fender / Joseph Brady / Bryan T. Hennessy /

Deborah A. McNamara / Elaine Kay / Henk M. Verheul / Neerincx Maarten / William M. Gallagher / Verena Murphy / Jochen H. M. Prehn / Miriam Koopman / Cornelis J. A. Punt / Fotios Loupakis / Matthias P. A. Ebert / Bauke Ylstra / Diether Lambrechts / Annette T. Byrne

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 16

Abstract: Increased copy number alterations, indicative of chromosomal instability, is associated with poor cancer outcome. Here, metastatic colorectal cancer patients displaying intermediate-high CIN associate with improved outcome following chemotherapy and ... ...

Abstract	Increased copy number alterations, indicative of chromosomal instability, is associated with poor cancer outcome. Here, metastatic colorectal cancer patients displaying intermediate-high CIN associate with improved outcome following chemotherapy and bevacizumab treatment, suggesting CIN as a predictive biomarker.
Keywords	Science ; Q
Language	English
Publishing date	2018-10-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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