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EGFR and colorectal cancer

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https://www.readbyqxmd.com/read/29333594/ras-testing-for-colorectal-cancer-patients-is-reliable-in-european-laboratories-that-pass-external-quality-assessment
#1
V Tack, M J L Ligtenberg, A G Siebers, P D M Rombout, P D Dabir, R D A Weren, J H J M van Krieken, E M C Dequeker
Wild-type status of KRAS and the NRAS gene (exon 2, 3, and 4) in the tumor should be determined before treatment of metastatic colorectal cancer (mCRC) patients with EGFR-targeting agents. There is a large variation in test methods to determine RAS status, and more sensitive detection methods were recently introduced. Data from quality assessment programs indicate substantial error rates. This study assessed the completeness and correctness of RAS testing in European laboratories that successfully passed external quality assessment (EQA)...
January 15, 2018: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/29327707/appendiceal-goblet-cell-carcinoids-and-adenocarcinomas-ex-goblet-cell-carcinoid-are-genetically-distinct-from-primary-colorectal-type-adenocarcinoma-of-the-appendix
#2
Moritz Jesinghaus, Björn Konukiewitz, Sebastian Foersch, Albrecht Stenzinger, Katja Steiger, Alexander Muckenhuber, Claudia Groß, Martin Mollenhauer, Wilfried Roth, Sönke Detlefsen, Wilko Weichert, Günter Klöppel, Nicole Pfarr, Anna Melissa Schlitter
The appendix gives rise to goblet cell carcinoids, which represent special carcinomas with distinct biological and histological features. Their genetic background and molecular relationship to colorectal adenocarcinoma is largely unknown. We therefore performed a next-generation sequencing analysis of 25 appendiceal carcinomas including 11 goblet cell carcinoids, 7 adenocarcinomas ex-goblet cell carcinoid, and 7 primary colorectal-type adenocarcinomas, using a modified Colorectal Cancer specific Panel comprising 32 genes linked to colorectal and neuroendocrine tumorigenesis...
January 12, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29326440/braf-inhibition-upregulates-a-variety-of-receptor-tyrosine-kinases-and-their-downstream-effector-gab2-in-colorectal-cancer-cell-lines
#3
Ricarda Herr, Sebastian Halbach, Miriam Heizmann, Hauke Busch, Melanie Boerries, Tilman Brummer
BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAFV600E oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated clinical trials that combine BRAF (and MEK) inhibitors, either singly or in combination, with the anti-EGFR antibodies cetuximab or panitumumab...
January 12, 2018: Oncogene
https://www.readbyqxmd.com/read/29312543/dual-targeting-of-her3-and-mek-may-overcome-her3-dependent-drug-resistance-of-colon-cancers
#4
Giulia Bon, Rossella Loria, Carla Azzurra Amoreo, Alessandra Verdina, Isabella Sperduti, Arianna Mastrofrancesco, Silvia Soddu, Maria Grazia Diodoro, Marcella Mottolese, Matilde Todaro, Giorgio Stassi, Michele Milella, Ruggero De Maria, Rita Falcioni
Although the medical treatment of colorectal cancer has evolved greatly in the last years, a significant portion of early-stage patients develops recurrence after therapies. The current clinical trials are directed to evaluate new drug combinations and treatment schedules. By the use of patient-derived or established colon cancer cell lines, we found that the tyrosine kinase receptor HER3 is involved in the mechanisms of resistance to therapies. In agreement, the immunohistochemical analysis of total and phospho-HER3 expression in 185 colorectal cancer specimens revealed a significant correlation with lower disease-free survival...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29312533/loss-of-pacs-2-delays-regeneration-in-dss-induced-colitis-but-does-not-affect-the-apcmin-model-of-colorectal-cancer
#5
Sarah L Dombernowsky, Jeanette Schwarz, Jacob Samsøe-Petersen, Reidar Albrechtsen, Kim B Jensen, Gary Thomas, Marie Kveiborg
PACS-2 is a multifunctional sorting protein that mediates cell homeostasis. We recently identified PACS-2 in a functional genome-wide siRNA screen for novel regulators of the metalloproteinase ADAM17, the main sheddase for ligands of the ErbB receptor family. Of note, we showed that Pacs2-/- mice have significantly reduced EGFR activity and proliferative index in the intestinal epithelium. As EGFR signaling is highly mitogenic for intestinal epithelial stem cells, and plays essential roles in intestinal epithelial regeneration and tumor development, we have now examined the role of PACS-2 in these processes...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29307989/gene-mutations-in-stool-from-gastric-and-colorectal-neoplasia-patients-by-next-generation-sequencing
#6
Omar Youssef, Virinder Sarhadi, Homa Ehsan, Tom Böhling, Monika Carpelan-Holmström, Selja Koskensalo, Pauli Puolakkainen, Arto Kokkola, Sakari Knuutila
AIM: To study cancer hotspot mutations by next-generation sequencing (NGS) in stool DNA from patients with different gastrointestinal tract (GIT) neoplasms. METHODS: Stool samples were collected from 87 Finnish patients diagnosed with various gastric and colorectal neoplasms, including benign tumors, and from 14 healthy controls. DNA was isolated from stools by using the PSP® Spin Stool DNA Plus Kit. For each sample, 20 ng of DNA was used to construct sequencing libraries using the Ion AmpliSeq Cancer Hotspot Panel v2 or Ion AmpliSeq Colon and Lung Cancer panel v2...
December 21, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29304903/locked-nucleic-acid-technology-for-highly-sensitive-detection-of-somatic-mutations-in-cancer
#7
Takayuki Ishige, Sakae Itoga, Kazuyuki Matsushita
The molecular diagnosis of the cancer mutational status is essential for modern clinical laboratory medicine. Mutations in EGFR, KRAS, BRAF, and PIK3CA genes are widely analyzed in solid tumors such as lung cancer, colorectal cancer, breast cancer, and melanoma. The allele-specific polymerase chain reaction, high-resolution melting, and Sanger sequencing are used for detecting and identifying gene mutations in many clinical laboratories. The locked nucleic acid (LNA) is a class of nucleic acid analogs that contain a methylene bridge connecting the 2' oxygen and 4' carbon in the ribose moiety...
2018: Advances in Clinical Chemistry
https://www.readbyqxmd.com/read/29304017/genotyping-of-kras-mutational-status-by-the-in-check-lab-on-chip-platform
#8
Maria Guarnaccia, Rosario Iemmolo, Floriana San Biagio, Enrico Alessi, Sebastiano Cavallaro
The KRAS oncogene is involved in the pathogenesis of several types of cancer, particularly colorectal cancer (CRC). The most frequent mutations in this gene are associated with poor survival, increased tumor aggressiveness and resistance to therapy with anti-epidermal growth factor receptor (EGFR) antibodies. For this reason, KRAS mutation testing has become increasingly common in clinical practice for personalized cancer treatments of CRC patients. Detection methods for KRAS mutations are currently expensive, laborious, time-consuming and often lack of diagnostic sensitivity and specificity...
January 5, 2018: Sensors
https://www.readbyqxmd.com/read/29301589/linking-foxo3-ncoa3-and-tcf7l2-to-ras-pathway-phenotypes-through-a-genome-wide-forward-genetic-screen-in-human-colorectal-cancer-cells
#9
Snehangshu Kundu, Muhammad Akhtar Ali, Niklas Handin, Narendra Padhan, Jimmy Larsson, Maria Karoutsou, Kenneth Ban, Jacek R Wiśniewski, Per Artursson, Liqun He, Mats Hellström, Tobias Sjöblom
BACKGROUND: The Ras pathway genes KRAS, BRAF, or ERBBs have somatic mutations in ~ 60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway or whether they have acquired mutations in genes hitherto unknown to belong to the pathway. METHODS: To address the second possibility and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted...
January 4, 2018: Genome Medicine
https://www.readbyqxmd.com/read/29299357/the-correlations-between-serum-amphiregulin-and-other-clinicopathological-factors-in-colorectal-cancer
#10
Chawalit Chayangsu, Siriporn Khunsri, Virote Sriuranpong, Suebpong Tanasanvimon
Background: Amphiregulin (AREG) is one of the epidermal growth factor receptor (EGFR) ligands and plays the important roles in tumor progression and metastasis. Upregulation of AREG in colorectal cancer (CRC) tissues has been shown to correlate with depth of tumor invasion, nerve invasion and liver metastasis. We sought to investigate a correlation of serum AREG in CRC with clinicopathological parameters. Methods: Patients with CRC receiving treatment at King Chulalongkorn Memorial Hospital during August 2013 to March 2014 were enrolled...
December 2017: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/29298682/sidedness-and-tp53-mutations-impact-os-in-anti-egfr-but-not-anti-vegf-treated-mcrc-an-analysis-of-the-kras-registry-of-the-agmt-arbeitsgemeinschaft-medikament%C3%A3-se-tumortherapie
#11
Florian Huemer, Josef Thaler, Gudrun Piringer, Hubert Hackl, Lisa Pleyer, Clemens Hufnagl, Lukas Weiss, Richard Greil
BACKGROUND: In metastatic colorectal cancer (mCRC), the localization of the primary tumour has been shown to be of prognostic as well as predictive relevance. METHODS: With the aim to investigate clinical and molecular disease characteristics with respect to sidedness in a real-world cohort, we analyzed 161 mCRC patients included in the KRAS Registry of the Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) between January 2006 and October 2013. RESULTS: Right-sided mCRC displayed a worse median overall survival (OS) in comparison to left-sided disease (18...
January 3, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29285234/targeted-next-generation-sequencing-in-chinese-colorectal-cancer-patients-guided-anti-egfr-treatment-and-facilitated-precision-cancer-medicine
#12
Helei Hou, Dong Liu, Chuantao Zhang, Yanxia Jiang, Guifang Lu, Na Zhou, Xiaonan Yang, Xiaoping Zhang, Zhuokun Li, Hongmei Zhu, Zhaoyang Qian, Xiaochun Zhang
Objective: Colorectal cancer (CRC) patients with both RAS and BRAF wild-type tumors determined by non-next generation sequencing (NGS) testing may still not respond due to the presence of additional mutated genes such as PIK3CA or PTEN. In this study, a broad, hybrid capture-based NGS assay was used to identify RAS, BRAF and additional targetable genetic alterations from Chinese CRC tissues. Methods: Fifty-seven cases of CRC were enrolled, and all the patients signed the informed consent...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29285233/aio-lq-0110-a-randomized-phase-ii-trial-comparing-oral-doxycycline-versus-local-administration-of-erythromycin-as-preemptive-treatment-strategies-of-panitumumab-mediated-skin-toxicity-in-patients-with-metastatic-colorectal-cancer
#13
Melanie Kripp, Nicole Prasnikar, Ursula Vehling-Kaiser, Julia Quidde, Salah-Eddin Al-Batran, Alexander Stein, Kai Neben, Carla Verena Hannig, Hans Werner Tessen, Tanja Trarbach, Axel Hinke, Ralf-Dieter Hofheinz
Background: Dermatologic toxicities, especially akne-like skin rash, are the most common side-effects associated with anti-epidermal growth factor receptor (EGFR) therapy. Preemptive treatment with oral tetracyclines is recommended as a standard. Topical prophylactic options have thus far not been compared to tetracyclines. In the current study, we sought to establish an alternative topical treatment. Patients and methods: In this multicentre, randomized, open-label phase II study patients with (K)Ras-wildtype colorectal cancer receiving panitumumab were randomized (1:1) to receive either doxycycline 100 mg b...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29279095/the-predictive-value-of-primary-tumor-location-in-patients-with-metastatic-colorectal-cancer-a-systematic-review
#14
REVIEW
Nele Boeckx, Katleen Janssens, Guy Van Camp, Marika Rasschaert, Konstantinos Papadimitriou, Marc Peeters, Ken Op de Beeck
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. It has been reported that left- and right-sided CRC harbor varying disease characteristics, which leads to a difference in prognosis and response to therapy. Recently, there have been retrospective studies about tumor location in metastatic CRC (mCRC) and its potential to predict the effect of anti-vascular endothelial growth factor and anti-epidermal growth factor receptor (anti-EGFR) therapies. In this review, we provide a comprehensive overview of the latest trials studying the predictive value of primary tumor location in mCRC and discuss biomarkers that might be associated with the differences in treatment response...
January 2018: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29273518/d2a-ala-peptide-derived-from-the-urokinase-receptor-exerts-anti-tumoural-effects-in-vitro-and-in-vivo
#15
Federico Furlan, Gabriele Eden, Marco Archinti, Ralitsa Arnaudova, Giuseppina Andreotti, Valentina Citro, Maria Vittoria Cubellis, Andrea Motta, Bernard Degryse
D2A-Ala is a synthetic peptide that has been created by introducing mutations in the original D2A sequence, 130IQEGEEGRPKDDR142 of human urokinase receptor (uPAR). In vitro, D2A-Ala peptide displays strong anti-tumoural properties inhibiting EGF-induced chemotaxis, invasion and proliferation of a human fibrosarcoma cell line, HT 1080, and a human colorectal adenocarcinoma cell line, HT 29. D2A-Ala exerts its effects by preventing EGF receptor (EGFR) phosphorylation. To test D2A-Ala in vivo, this peptide was PEGylated generating polyethyleneglycol (PEG)-D2A-Ala peptide...
December 19, 2017: Peptides
https://www.readbyqxmd.com/read/29259073/phase-ii-study-of-panitumumab-in-ras-wild-type-metastatic-adenocarcinoma-of-small-bowel-or-ampulla-of-vater
#16
Pat Gulhati, Kanwal Raghav, Rachna Shroff, Gauri Varadhachary, Milind Javle, Wei Qiao, Huamin Wang, Jeffrey Morris, Robert Wolff, Michael J Overman
LESSONS LEARNED: Panitumumab has no clinical activity in metastatic RAS wild-type small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC), possibly due to the foregut and midgut derivation of small bowel and ampulla.These results, along with findings from genomic characterization of SBA, suggest that SBA represents a unique intestinal malignancy and treatments should not be habitually extrapolated from colorectal cancer.Further studies evaluating the benefit of targeted therapies exclusively in SBA and AAC are warranted...
December 19, 2017: Oncologist
https://www.readbyqxmd.com/read/29242316/colorectal-cancer-consensus-molecular-subtypes-translated-to-preclinical-models-uncover-potentially-targetable-cancer-cell-dependencies
#17
Anita Sveen, Jarle Bruun, Peter W Eide, Ina A Eilertsen, Lorena Ramirez, Astrid Murumägi, Mariliina A Arjama, Stine A Danielsen, Kushtrim Kryeziu, Elena Elez, Josep Tabernero, Justin Guinney, Hector G Palmer, Arild Nesbakken, Olli Kallioniemi, Rodrigo Dienstmann, Ragnhild A Lothe
PURPOSE: Response to standard oncological treatment is limited in colorectal cancer (CRC). The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing, however, drug discovery is currently limited by the lack of translation of CMS to preclinical models. EXPERIMENTAL DESIGN: We analyzed CMS in primary CRCs, cell lines and patient-derived xenografts (PDXs). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n=459 drugs) to analyze subtype-specific drug sensitivities...
December 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29222171/tankyrase-inhibition-enhances-the-anti-proliferative-effect-of-pi3k-and-egfr-inhibition-mutually-affecting-%C3%AE-catenin-and-akt-signaling-in-colorectal-cancer
#18
Nina T Solberg, Jo Waaler, Kaja Lund, Line Mygland, Petter A Olsen, Stefan Krauss
Over-activation of the WNT/β-catenin signaling axis is a common denominator in colorectal cancer (CRC). Currently there is no available WNT inhibitor in clinical practice. Although tankyrase inhibitors have been proposed as promising candidates there are many CRC models that do not respond positively to tankyrase inhibition in vitro and in vivo. Therefore, a combinatorial therapeutic approach combining a tankyrase inhibitor (G007-LK) with PI3K (BKM120) and EGFR (Erlotinib) inhibitors in CRC was investigated...
December 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29222163/novel-in-vitro-cancer-models-for-optimizing-anti-egfr-therapies
#19
Stefania Napolitano, Fortunato Ciardiello
Pre-clinical models, that are able to recapitulate the biology and pathology of the original individual cancer, are needed to better investigate mechanisms of response and resistance to anticancer therapies. In this respect, novel in vitro models for metastatic colorectal cancer could be of high value.
December 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29212194/association-between-mir-31-3p-expression-and-cetuximab-efficacy-in-patients-with-kras-wild-type-metastatic-colorectal-cancer-a-post-hoc-analysis-of-the-new-epoc-trial
#20
Siân Pugh, Raphaële Thiébaut, John Bridgewater, Marie-Lise Grisoni, Karwan Moutasim, Francis Rousseau, Gareth J Thomas, Gareth Griffiths, François Liebaert, John Primrose, Pierre Laurent-Puig
Background: High miR-31-3p expression is associated with inferior outcomes in KRAS wild-type (WT) advanced colorectal cancer patients treated with anti-EGFR therapy. This study evaluated miR-31-3p expression in patients with operable colorectal liver metastases (LM) enrolled in the New EPOC study. Methods: MiR-31-3p expression was measured in primary tumors (PT) from 149 KRAS WT patients including 71 receiving chemotherapy alone (CT) and 78 receiving chemotherapy plus cetuximab (CTX)...
November 7, 2017: Oncotarget
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