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https://www.readbyqxmd.com/read/29158469/molecular-basis-for-necitumumab-inhibition-of-egfr-variants-associated-with-acquired-cetuximab-resistance
#1
Atrish Bagchi, Jaafar N Haidar, Scott W Eastman, Michal Vieth, Michael Topper, Michelle D Iacolina, Jason M Walker, Amelie Forest, Yang Shen, Ruslan D Novosiadly, Kathryn M Ferguson
Acquired resistance to cetuximab, an antibody that targets the epidermal growth factor receptor (EGFR), impacts clinical benefit in head and neck, and colorectal cancers (CRC). One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that necitumumab, another FDA approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab resistance substitution, S468R (or S492R, depending on the amino acid numbering system)...
November 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29156800/comparative-molecular-analyses-of-left-sided-colon-right-sided-colon-and-rectal-cancers
#2
Mohamed E Salem, Benjamin A Weinberg, Joanne Xiu, Wafik S El-Deiry, Jimmy J Hwang, Zoran Gatalica, Philip A Philip, Anthony F Shields, Heinz-Josef Lenz, John L Marshall
Tumor sidedness has emerged as an important prognostic and predictive factor in the treatment of colorectal cancer. Recent studies demonstrate that patients with advanced right-sided colon cancers have a worse prognosis than those with left-sided colon or rectal cancers, and these patient subgroups respond differently to biological therapies. Historically, management of patients with metastatic colon and rectal cancers has been similar, and colon and rectal cancer patients have been grouped together in large clinical trials...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156678/epigenetic-silencing-of-tumor-suppressor-candidate-3-confers-adverse-prognosis-in-early-colorectal-cancer
#3
Elke Burgermeister, Patrick Höde, Johannes Betge, Tobias Gutting, Andreas Merkel, Wen Wu, Marc Tänzer, Maximilian Mossner, Daniel Nowak, Julia Magdeburg, Felix Rückert, Carsten Sticht, Katja Breitkopf-Heinlein, Nadine Schulte, Nicolai Härtel, Sebastian Belle, Stefan Post, Timo Gaiser, Barbara Ingold Heppner, Hans-Michael Behrens, Christoph Röcken, Matthias P A Ebert
Colorectal cancer (CRC) is a biologically and clinically heterogeneous disease. Even though many recurrent genomic alterations have been identified that may characterize distinct subgroups, their biological impact and clinical significance as prognostic indicators remain to be defined. The tumor suppressor candidate-3 (TUSC3/N33) locates to a genomic region frequently deleted or silenced in cancers. TUSC3 is a subunit of the oligosaccharyltransferase (OST) complex at the endoplasmic reticulum (ER) which catalyzes bulk N-glycosylation of membrane and secretory proteins...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156521/micrornas-as-novel-biomarkers-for-colorectal-cancer-new-outlooks
#4
REVIEW
Naghmeh Shirafkan, Behzad Mansoori, Ali Mohammadi, Navid Shomali, Mehri Ghasbi, Behzad Baradaran
Colorectal cancer is one of the most prevalent cancers with high mortality in the world. MicroRNAs are a class of small non-coding RNAs that regulate gene expression through targeting mRNAs. MicroRNAs involve in many biological and pathological processes such as cell growth, differentiation, apoptosis. etc. Dysregulation of miRNAs expression patterns have been reported in many tumors including Colorectal Cancer. Various studies indicate that miRNAs can be utilized as diagnostic and prognostic biomarkers for evaluation of tumor initiation, development, invasion, metastasis and response to chemotherapeutic drugs...
November 14, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29152115/hdac-4-regulates-claudin-2-expression-in-egfr-erk1-2-dependent-manner-to-regulate-colonic-epithelial-cell-differentiation
#5
Rizwan Ahmad, Balawant Kumar, Kaichao Pan, Punita Dhawan, Amar B Singh
In normal colon, claudin-2 expression is restricted to the crypt bottom containing the undifferentiated and proliferative colonocytes. Claudin-2 expression is also upregulated in colorectal cancer (CRC) and promotes carcinogenesis. However, cellular mechanism/s regulated by increased claudin-2 expression during the CRC and mechanism/s regulating this increase remain poorly understood. Epigenetic mechanisms help regulate expression of cancer-associated genes and inhibition of Histone Deacetylases (HDACs) induces cell cycle arrest and differentiation...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29149105/lgr5-expression-is-regulated-by-egf-in-early-colorectal-adenomas-and-governs-egfr-inhibitor-sensitivity
#6
R G Morgan, E Mortensson, D N Legge, B Gupta, T J Collard, A Greenhough, A C Williams
BACKGROUND: LGR5 serves as a co-receptor for Wnt/β-catenin signalling and marks normal intestinal stem cells; however, its role in colorectal cancer (CRC) remains controversial. LGR5(+) cells are known to exist outside the stem cell niche during CRC progression, and the requirement for epidermal growth factor (EGF) signalling within early adenomas remains to be fully elucidated. METHODS: Epidermal growth factor and gefitinib treatments were performed in EGF-responsive LGR5(+) early adenoma RG/C2 cells...
November 16, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29140271/molecular-targeted-therapies-for-epidermal-growth-factor-receptor-and-its-resistance-mechanisms
#7
REVIEW
Toshimitsu Yamaoka, Motoi Ohba, Tohru Ohmori
Cancer therapies targeting epidermal growth factor receptor (EGFR), such as small-molecule kinase inhibitors and monoclonal antibodies, have been developed as standard therapies for several cancers, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, breast cancer, and squamous cell carcinoma of the head and neck. Although these therapies can significantly prolong progression-free survival, curative effects are not often achieved because of intrinsic and/or acquired resistance. The resistance mechanisms to EGFR-targeted therapies can be categorized as resistant gene mutations, activation of alternative pathways, phenotypic transformation, and resistance to apoptotic cell death...
November 15, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29138581/puma-mediates-the-anti-cancer-effect-of-osimertinib-in-colon-cancer-cells
#8
Lingchuan Guo, Shan Huang, Xinwei Wang
Osimertinib, an irreversible EGFR/HER2 inhibitor, has been found to be effective in the cancer cell with EGFR gene mutations in preclinical lung cancer models. However, the effect of osimertinib in colorectal cancer (CRC) cells is unclear. In the present study, we investigated how osimertinib suppresses CRC cells growth and potentiates effects of other chemotherapeutic drugs. We found that p73-mediated osimertinib-induced p53 upregulated modulator of apoptosis (PUMA) expression irrespective of p53 status following PI3K/AKT pathway inhibition in CRC cells...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29137388/rapid-and-accurate-detection-of-kras-mutations-in-colorectal-cancers-using-the-isothermal-based-optical-sensor-for-companion-diagnostics
#9
Choong Eun Jin, Seung-Seop Yeom, Bonhan Koo, Tae Yoon Lee, Jeong Hoon Lee, Yong Shin, Seok-Byung Lim
Although KRAS mutational status testing is becoming a companion diagnostic tool for managing patients with colorectal cancer (CRC), there are still several difficulties when analyzing KRAS mutations using the existing assays, particularly with regard to low sensitivity, its time-consuming, and the need for large instruments. We developed a rapid, sensitive, and specific mutation detection assay based on the bio-photonic sensor termed ISAD (isothermal solid-phase amplification/detection), and used it to analyze KRAS gene mutations in human clinical samples...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29137301/antitumor-efficacy-of-triple-monoclonal-antibody-inhibition-of-epidermal-growth-factor-receptor-egfr-with-mm151-in-egfr-dependent-and-in-cetuximab-resistant-human-colorectal-cancer-cells
#10
Stefania Napolitano, Giulia Martini, Erika Martinelli, Carminia Maria Della Corte, Floriana Morgillo, Valentina Belli, Claudia Cardone, Nunzia Matrone, Fortunato Ciardiello, Teresa Troiani
Purpose: We investigated the effect of triple monoclonal antibody inhibition of EGFR to overcome acquired resistance to first generation of anti-EGFR inhibitors. Experimental design: MM151 is a mixture of three different monoclonal IgG1 antibodies directed toward three different, non-overlapping, epitopes of the EGFR. We performed an in vivo study by using human CRC cell lines (SW48, LIM 1215 and CACO2) which are sensitive to EGFR inhibitors, in order to evaluate the activity of MM151 as compared to standard anti-EGFR mAbs, such as cetuximab, as single agent or in a sequential strategy of combination MM151 with irinotecan (induction therapy) followed by MM151 with a selective MEK1/2 inhibitor (MEKi) (maintenance therapy)...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29136952/identification-and-validation-of-cetuximab-resistance-associated-long-noncoding-rna-biomarkers-in-metastatic-colorectal-cancer
#11
Ke Peng, Ruiqi Liu, Yiyi Yu, Li Liang, Shan Yu, Xiaojing Xu, Tianshu Liu
BACKGROUND: Cetuximab is one of the most widely used epidermal growth factor receptor (EGFR) inhibitors to treat patients with metastatic colorectal cancer (mCRC) harboring wild-type of RAS/RAF status. However, primary and acquired resistance to cetuximab is often found during target therapy. METHODS: To gain insights into the functions of long non-coding RNA (lncRNA) in cetuximab resistance, we used a lncRNA-mining approach to distinguish lncRNA specific probes in Affymetrix HG-U133A 2...
November 10, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29135755/management-of-skin-toxicity-caused-by-epidermal-growth-factor-receptor-inhibitors-an-evidence-based-implementation-project
#12
Xiaolu Guo, Micah D J Peters, Zhenqi Lu
BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) bind to and inhibit epidermal growth factor receptors (EGFRs) in cancer cells, slowing/preventing tumor growth. As a type of "targeted therapy", they have demonstrated therapeutic effects on solid tumors including colorectal, lung, and head and neck cancers. While effective, various skin reactions are associated with EGFRI therapy which can lead to dose modification or discontinuation as well as discomfort, pain and reduced quality of life...
November 2017: JBI Database of Systematic Reviews and Implementation Reports
https://www.readbyqxmd.com/read/29133621/the-mutational-landscape-of-gastrointestinal-malignancies-as-reflected-by-circulating-tumor-dna
#13
Paul Riviere, Paul T Fanta, Sadakatsu Ikeda, Joel Baumgartner, Gregory M Heestand, Razelle Kurzrock
We aimed to assess the utility of a novel, non-invasive method of detecting genomic alterations in patients with gastrointestinal malignancies i.e., the use of liquid biopsies to obtain blood-derived circulating tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers. The most common cancer types were colorectal adenocarcinoma (N=55 (26%)), appendiceal adenocarcinoma (N=46 (22%)), hepatocellular carcinoma (N=31 (15%)), and pancreatic ductal adenocarcinoma (N=25 (12%))...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29129559/treatment-and-survival-outcome-of-braf-mutated-metastatic-colorectal-cancer-a-retrospective-matched-case-control-study
#14
Hamzeh Kayhanian, Emily Goode, Francesco Sclafani, Joo Ern Ang, Marco Gerlinger, David Gonzalez de Castro, Scott Shepherd, Clare Peckitt, Sheela Rao, David Watkins, Ian Chau, David Cunningham, Naureen Starling
BACKGROUND: Somatic v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation, present in approximately 10% of metastatic colorectal cancer (mCRC) cases, is associated with poor prognosis. Patient outcome outside of clinical trials has only been reported in small series. We report real-world data on treatment and survival for BRAF-mutated (MT) patients at a single tertiary center, compared with a matched BRAF wild type (WT) control group. PATIENTS AND METHODS: All colorectal cancer patients tested for BRAF mutation, from October 2010 to November 2014 were identified...
October 16, 2017: Clinical Colorectal Cancer
https://www.readbyqxmd.com/read/29125233/in-vivo-imaging-xenograft-models-for-the-evaluation-of-anti-brain-tumor-efficacy-of-targeted-drugs
#15
Kenji Kita, Sachiko Arai, Akihiro Nishiyama, Hirokazu Taniguchi, Koji Fukuda, Rong Wang, Tadaaki Yamada, Shinji Takeuchi, Shoichiro Tange, Atsushi Tajima, Mitsutoshi Nakada, Kazuo Yasumoto, Yoshiharu Motoo, Takashi Murakami, Seiji Yano
Molecular-targeted drugs are generally effective against tumors containing driver oncogenes, such as EGFR, ALK, and NTRK1. However, patients harboring these oncogenes frequently experience a progression of brain metastases during treatment. Here, we present an in vivo imaging model for brain tumors using human cancer cell lines, including the EGFR-L858R/T790M-positive H1975 lung adenocarcinoma cells, the NUGC4 hepatocyte growth factor (HGF)-dependent gastric cancer cells, and the KM12SM colorectal cancer cells containing the TPM3-NTRK1 gene fusion...
November 10, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/29122835/multiple-hotspot-mutations-scanning-by-single-droplet-digital-pcr
#16
Charles Decraene, Amanda Silveira, François-Clément Bidard, Audrey Vallee, Marc Michel, Samia Melaabi, Anne Vincent-Salomon, Adrien Saliou, Alexandre Houy, Maud Milder, Olivier Lantz, Marc Ychou, Marc G Denis, Jean-Yves Pierga, Marc-Henri Stern, Charlotte Proudhon
BACKGROUND: Progress in the liquid biopsy field, combined with the development of droplet digital PCR (ddPCR)(12), has enabled noninvasive monitoring of mutations with high detection accuracy. However, current assays detect a restricted number of mutations per reaction. ddPCR is a recognized method for detecting alterations previously characterized in tumor tissues, but its use as a discovery tool when the mutation is unknown a priori remains limited. METHODS: We established 2 ddPCR assays detecting all genomic alterations within KRAS() exon 2 and EGFR exon 19 mutation hotspots, which are of clinical importance in colorectal and lung cancer, with use of a unique pair of TaqMan® oligoprobes...
November 9, 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/29115941/microrna-193a-3p-is-specifically-down-regulated-and-acts-as-a-tumor-suppressor-in-braf-mutated-colorectal-cancer
#17
Hidekazu Takahashi, Masanobu Takahashi, Shinobu Ohnuma, Michiaki Unno, Yuki Yoshino, Kota Ouchi, Shin Takahashi, Yasuhide Yamada, Hideki Shimodaira, Chikashi Ishioka
BACKGROUND: The aim of this study was to identify miRNAs specifically dysregulated in BRAF-mutated colorectal cancer, which could lead to a better understanding of the molecular mechanisms underlying oncogenesis of this malignant subtype of colorectal cancer. METHODS: Candidate dysregulated miRNAs were selected in genome-wide miRNA expression array analysis using a screening set composed of 15 BRAF-mutated and 15 non-KRAS/BRAF-mutated colorectal cancers. The miRNA expressions were validated in another set of patients...
November 7, 2017: BMC Cancer
https://www.readbyqxmd.com/read/29111094/real-time-pcr-based-method-for-the-rapid-detection-of-extended-ras-mutations-using-bridged-nucleic-acids-in-colorectal-cancer
#18
Takao Iida, Yukie Mizuno, Yasuharu Kaizaki
Mutations in RAS and BRAF are predictors of the efficacy of anti-epidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer (mCRC). Therefore, simple, rapid, cost-effective methods to detect these mutations in the clinical setting are greatly needed. In the present study, we evaluated BNA Real-time PCR Mutation Detection Kit Extended RAS (BNA Real-time PCR), a real-time PCR method that uses bridged nucleic acid clamping technology to rapidly detect mutations in RAS exons 2-4 and BRAF exon 15...
October 27, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29100436/meta-analysis-of-the-mutational-status-of-circulation-tumor-cells-and-paired-primary-tumor-tissues-from-colorectal-cancer-patients
#19
Yong Liu, Stefano Meucci, Liming Sheng, Ulrich Keilholz
As predictive markers for anti-EGFR therapy, KRAS and BRAF mutations are routinely detected in primary and metastatic colorectal cancer (CRC) cells, but seldom in circulating tumor cells (CTCs). Detecting mutations in CTCs could help explain mutational differences between tumor cells at local sites and distant metastases, thereby improving treatment outcomes. Here, we conducted a systematic review and meta-analysis to compare KRAS and BRAF mutations in paired CTCs and primary tumors from CRC patients, to detect any possible discordance...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29094026/establishing-a-colorectal-cancer-liver-metastasis-patient-derived-tumor-xenograft-model-for-the-evaluation-of-personalized-chemotherapy
#20
Joohee Jung, Jisup Kim, Hyun Kyung Lim, Kyoung Mee Kim, Yun Sun Lee, Joon Seong Park, Dong Sup Yoon
Purpose: In order to suggest optimal anticancer drugs for patient-tailored chemotherapy, we developed a colorectal cancer (CRC)-liver metastasis patient-derived tumor xenograft (PDTX) model. Methods: Tissue obtained from a patient with CRC-liver metastasis (F0) was transplanted in a nonobese female mouse with diabetic/severe combined immune deficiency (F1) and the tumor tissue was retransplanted into nude mice (F2). When tumor volumes reached ~500 mm(3), the F2 mice were randomly divided into 4 groups (n = 4/group) of doxorubicin, cisplatin, docetaxel, and nontreated control groups...
October 2017: Annals of Surgical Treatment and Research
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