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EGFR and colorectal cancer

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https://www.readbyqxmd.com/read/28432610/left-versus-right-does-location-matter-for-refractory-metastatic-colorectal-cancer-patients-in-phase-1-clinical-trials
#1
Sukeshi Patel Arora, Norma S Ketchum, Joel Michalek, Jonathon Gelfond, Devalingam Mahalingam
PURPOSE: Location of the primary tumor is prognostic and predictive of efficacy with VEGF-inhibitors (I) versus EGFR-I given first-line to metastatic colorectal cancer (mCRC) patients. However, little is known regarding the effect of location on prognosis and prediction in refractory mCRC. We assessed the efficacy of VEGF-I and EGFR-I in regards to location of the primary tumor in patients with refractory mCRC enrolled in early phase studies. METHODS: A historical cohort analysis of mCRC patients, including 44 phase I trials our institution, from March 2004 to September 2012...
April 22, 2017: Journal of Gastrointestinal Cancer
https://www.readbyqxmd.com/read/28432289/simultaneous-detection-of-egfr-and-vegf-in-colorectal-cancer-using-fluorescence-raman-endoscopy
#2
Yong-Il Kim, Sinyoung Jeong, Kyung Oh Jung, Myung Geun Song, Chul-Hee Lee, Seock-Jin Chung, Ji Yong Park, Myeong Geun Cha, Sung Gun Lee, Bong-Hyun Jun, Yun-Sang Lee, Do Won Hwang, Hyewon Youn, Keon Wook Kang, Yoon-Sik Lee, Dae Hong Jeong, Dong Soo Lee
Fluorescence endomicroscopy provides quick access to molecular targets, while Raman spectroscopy allows the detection of multiple molecular targets. Using a simultaneous fluorescence-Raman endoscopic system (FRES), we herein demonstrate its potential in cancer diagnosis in an orthotopically induced colorectal cancer (CRC) xenograft model. In the model, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) were targeted with antibody-conjugated fluorescence and surface-enhanced Raman scattering (F-SERS) dots...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28424201/pik3ca-mutations-contribute-to-acquired-cetuximab-resistance-in-metastatic-colorectal-cancer-patients
#3
Jian Ming Xu, Yan Wang, You-Liang Wang, Yan Wang, Tao Liu, Ming Ni, Man-Sheng Li, Li Lin, Fei-Jiao Ge, Chun Gong, Jun-Yan Gu, Ru Jia, He-Fei Wang, Yu Ling Chen, Rong-Rui Liu, Chuan-Hua Zhao, Zhao-Li Tan, Yang Jin, Yunping Zhu, Shuji Ogino, Zhi Rong Qian
<p>Mutations in KRAS are considered to be the main drivers of acquired resistance to epidermal growth factor receptor (EGFR) blockade in patients with metastatic colorectal cancer (mCRC). However, the potential roles of other genes downstream of the EGFR signaling pathway in conferring acquired resistance has not been extensively investigated.</p> <br /><br />Experimental Design: <p>Using circulating tumor DNA (ctDNA) from patients with mCRC and with acquired cetuximab resistance, we developed a targeted amplicon ultra-deep sequencing method to screen for low-abundance somatic mutations in a panel of genes that encode components of the EGFR signaling pathway...
April 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28423516/the-addition-of-celecoxib-improves-the-antitumor-effect-of-cetuximab-in-colorectal-cancer-role-of-egfr-ras-foxm1-%C3%AE-catenin-signaling-axis
#4
Araceli Valverde, Jon Peñarando, Amanda Cañas, Laura M López-Sánchez, Francisco Conde, Silvia Guil-Luna, Vanessa Hernández, Carlos Villar, Cristina Morales-Estévez, Juan de la Haba-Rodríguez, Enrique Aranda, Antonio Rodríguez-Ariza
Here we showed that the addition of the COX-2 inhibitor celecoxib improved the antitumor efficacy in colorectal cancer (CRC) of the monoclonal anti-EGFR antibody cetuximab. The addition of celecoxib augmented the efficacy of cetuximab to inhibit cell proliferation and to induce apoptosis in CRC cells. Moreover, the combination of celecoxib and cetuximab was more effective than either treatment alone in reducing the tumor volume in a mouse xenograft model. The combined treatment enhanced the inhibition of EGFR signaling and altered the subcellular distribution of β-catenin...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422758/first-in-human-trial-of-multikinase-vegf-inhibitor-regorafenib-and-anti-egfr-antibody-cetuximab-in-advanced-cancer-patients
#5
Vivek Subbiah, Muhammad Rizwan Khawaja, David S Hong, Behrang Amini, Jiang Yungfang, Hui Liu, Adrienne Johnson, Alexa B Schrock, Siraj M Ali, James X Sun, David Fabrizio, Sarina Piha-Paul, Siqing Fu, Apostolia M Tsimberidou, Aung Naing, Filip Janku, Daniel D Karp, Michael Overman, Cathy Eng, Scott Kopetz, Funda Meric-Bernstam, Gerald S Falchook
BACKGROUND: The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC). METHODS: Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC...
April 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28422714/toll-like-receptor-3-as-an-immunotherapeutic-target-for-kras-mutated-colorectal-cancer
#6
Radhashree Maitra, Titto Augustine, Yitzchak Dayan, Carol Chandy, Matthew Coffey, Sanjay Goel
New therapeutic interventions are essential for improved management of patients with metastatic colorectal cancer (mCRC). This is especially critical for those patients whose tumors harbor a mutation in the KRAS oncogene (40-45% of all patients). This patient cohort is excluded from receiving anti-EGFR monoclonal antibodies that have added a significant therapeutic benefit for KRAS wild type CRC patients. Reovirus, a double stranded (ds) RNA virus is in clinical development for patients with chemotherapy refractory KRAS mutated tumors...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28419195/plasma-ctdna-ras-mutation-analysis-for-the-diagnosis-and-treatment-monitoring-of-metastatic-colorectal-cancer-patients
#7
J Vidal, L Muinelo, A Dalmases, F Jones, D Edelstein, M Iglesias, M Orrillo, A Abalo, C Rodríguez, E Brozos, Y Vidal, S Candamio, F Vázquez, J Ruiz, M Guix, L Visa, V Sikri, J Albanell, B Bellosillo, R López, C Montagut
Background: RAS assessement is mandatory for therapy decision in metastatic colorectal cancer (mCRC) patients. This determination is based on tumor tissue, however genotyping of circulating tumor (ct)DNA offers clear advantages as a minimally invasive method that represents tumor heterogeneity. Our study aims to evaluate the use of ctDNA as an alternative determining baseline RAS status and subsequent monitoring of RAS mutations during therapy as a component of routine clinical practice...
April 13, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28418857/multi-factorial-modulation-of-colorectal-carcinoma-cells-motility-partial-coordination-by-the-tetraspanin-co-029-tspan8
#8
Yingying Zhu, Naouel Ailane, Monica Sala-Valdés, Farhad Haghighi-Rad, Martine Billard, Viet Nguyen, Raphael Saffroy, Antoinette Lemoine, Eric Rubinstein, Claude Boucheix, Céline Greco
Colorectal carcinoma cells Isreco1 display an ability to migrate controlled by a complex set of signals issued from the membrane. By comparing cells infected by mycoplasmas and mycoplasmas free cells, we have established that basal 2D migration is dependent on a double signal mediated by the collagen receptors integrins alpha1/2 and the Toll-Like receptor TLR2. The signal issued from mycoplasmas can be replaced by a TLR2 ligand and the functional effect is neutralized by silencing of MyD88. Following previous observation that downregulation of E-cadherin/p120 catenin increases cell motility, we now report that EGFR or CD44 inhibition have a similar effect on cell motility that is restricted to tetraspanin Co-029/tspan8 transduced IsrecoI cells (Is1-Co029)...
April 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28407239/the-therapeutic-potential-of-targeting-the-braf-in-patients-with-colorectal-cancer
#9
REVIEW
Afsane Bahrami, AmirReza Hesari, Majid Khazaei, Seyed Mahdi Hassanian, Gordon Ferns, Amir Avan
Colorectal cancer is among the most lethal malignancies globally. BRAF is a member of the RAS/RAF/MEK/ERK signaling pathway. Its constitutive activation can result in increased cellular growth, development, invasion, and resistance to therapy. A mutation of the BRAF gene is present in 5-10% of metastatic colorectal cancers. BRAF mutations have been found to predict a lack of benefit to anti-EGFR therapy in metastatic CRC. Furthermore, CRC containing the BRAF V600E mutation display an innate resistance to BRAF inhibitors...
April 13, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28407110/prognostic-and-predictive-value-of-primary-tumour-side-in-patients-with-ras-wild-type-metastatic-colorectal-cancer-treated-with-chemotherapy-and-egfr-directed-antibodies-in-six-randomised-trials
#10
D Arnold, B Lueza, J-Y Douillard, M Peeters, H-J Lenz, A Venook, V Heinemann, E Van Cutsem, J-P Pignon, J Tabernero, A Cervantes, F Ciardiello
Background: There is increasing evidence that metastatic colorectal cancer (mCRC) is a genetically heterogeneous disease and that tumours arising from different sides of the colon (left versus right) have different clinical outcomes. Furthermore, previous analyses comparing the activity of different classes of targeted agents in patients with KRAS wild-type (wt) or RAS wt mCRC suggest that primary tumour location (side), might be both prognostic and predictive for clinical outcome. Methods: This retrospective analysis investigated the prognostic and predictive influence of the localisation of the primary tumour in patients with unresectable RAS wt mCRC included in six randomised trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181), comparing chemotherapy plus EGFR antibody therapy (experimental arm) with chemotherapy or chemotherapy and bevacizumab (control arms)...
April 12, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28404754/therapeutic-response-of-metastatic-colorectal-cancer-harboring-a-kras-missense-mutation-after-combination-chemotherapy-with-the-egfr-inhibitor-panitumumab
#11
Emil Lou, Donna D'Souza, Andrew C Nelson
Over the past decade, subset analyses of retrospective and prospective clinical studies have determined that KRAS-mutated metastatic colorectal cancers do not respond effectively to inhibition of epidermal growth factor receptor (EGFR) with the EGFR-targeting monoclonal antibodies cetuximab or panitumumab. Within the past few years, the scope of tested variants in the KRAS oncogene has expanded significantly, and testing of all RAS family genes has become more widely available in clinical laboratories. Expert consensus guidelines have recommended not using EGFR inhibitors in patients with KRAS-mutated tumors...
April 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28400195/egfr-in-tumor-associated-myeloid-cells-promotes-development-of-colorectal-cancer-in-mice-and-associates-with-outcomes-of-patients
#12
Sriram Srivatsa, Mariel C Paul, Claudia Cardone, Martin Holcmann, Nicole Amberg, Paulina Pathria, Michaela A Diamanti, Markus Linder, Gerald Timelthaler, Hans P Dienes, Lukas Kenner, Fritz Wrba, Gerald W Prager, Stefan Rose-John, Robert Eferl, Giuseppina Liguori, Gerardo Botti, Erika Martinelli, Florian R Greten, Fortunato Ciardiello, Maria Sibilia
BACKGROUND & AIMS: Inhibitors of the epidermal growth factor receptor (EGFR) are the first-line therapy for patients with metastatic colorectal tumors without RAS mutations. However, EGFR inhibitors are ineffective in these patients, and tumor level of EGFR does not associate with response to therapy. We screened human colorectal tumors for EGFR-positive myeloid cells and investigated their association with patient outcome. We also performed studies in mice to evaluate how EGFR expression in tumor cells and myeloid cells contributes to development of colitis-associated cancer and ApcMin-dependent intestinal tumorigenesis...
April 8, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28398227/miniaturized-real-time-pcr-on-a-q3-system-for-rapid-kras-genotyping
#13
Maria Guarnaccia, Rosario Iemmolo, Salvatore Petralia, Sabrina Conoci, Sebastiano Cavallaro
Colorectal cancer (CRC) is an aggressive human malignancy with a complex genomic landscape harboring KRAS mutations. In 40%-60% of patients with CRC, constantly active KRAS proteins affect the prognosis, surgical strategy, and clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) agents. For this reason, there is a greater demand for minimally-invasive diagnostic devices to characterize the genetic pattern and prevent the acquired mechanism to drug resistance. The rapid developments in cutting-edge diagnostic techniques are expected to play a growing role in medicine and represent an attractive promise to identify potential responders to personalized medicine...
April 11, 2017: Sensors
https://www.readbyqxmd.com/read/28393575/using-circulating-cell-free-dna-to-monitor-personalized-cancer-therapy
#14
Michael Oellerich, Ekkehard Schütz, Julia Beck, Philipp Kanzow, Piers N Plowman, Glen J Weiss, Philip D Walson
High-quality genomic analysis is critical for personalized pharmacotherapy in patients with cancer. Tumor-specific genomic alterations can be identified in cell-free DNA (cfDNA) from patient blood samples and can complement biopsies for real-time molecular monitoring of treatment, detection of recurrence, and tracking resistance. cfDNA can be especially useful when tumor tissue is unavailable or insufficient for testing. For blood-based genomic profiling, next-generation sequencing (NGS) and droplet digital PCR (ddPCR) have been successfully applied...
April 10, 2017: Critical Reviews in Clinical Laboratory Sciences
https://www.readbyqxmd.com/read/28382467/plasticity-of-resistance-and-sensitivity-to-anti-epidermal-growth-factor-receptor-inhibitors-in-metastatic-colorectal-cancer
#15
Andrea Sartore-Bianchi, Salvatore Siena
Colorectal cancer (CRC) is one of the most prevalent cancers and the second leading cause of cancer mortality worldwide. Survival in the metastatic setting has been gradually improved by the addition to cytotoxic chemotherapy of agents targeting the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Considerable heterogeneity exists within CRC due to the varied genetic and epigenetic mechanisms involved in differing pathways of carcinogenesis. The knowledge of molecular abnormalities underlying colorectal tumourigenesis and the progression of dysplastic precursors to invasive and ultimately metastatic lesions has advanced in recent years by comprehensive sequencing studies...
April 6, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28376221/efficacy-of-nedd8-pathway-inhibition-in-preclinical-models-of-poorly-differentiated-clinically-aggressive-colorectal-cancer
#16
Gabriele Picco, Consalvo Petti, Francesco Sassi, Katia Grillone, Giorgia Migliardi, Teresa Rossi, Claudio Isella, Federica Di Nicolantonio, Ivana Sarotto, Anna Sapino, Alberto Bardelli, Livio Trusolino, Andrea Bertotti, Enzo Medico
Background: The NEDD8 conjugation pathway modulates the ubiquitination and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of response predictors are still missing. Methods: We investigated in vitro sensitivity to pevonedistat in 122 colorectal cancer (CRC) cell lines by an ATP-based proliferation assay and evaluated apoptosis and DNA content by flow cytometry...
February 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28368441/concordance-of-blood-and-tumor-based-detection-of-ras-mutations-to-guide-anti-egfr-therapy-in-metastatic-colorectal-cancer
#17
J Grasselli, E Elez, G Caratù, J Matito, C Santos, T Macarulla, J Vidal, M Garcia, J M Viéitez, D Paéz, E Falcó, C Lopez Lopez, E Aranda, F Jones, V Sikri, P Nuciforo, R Fasani, J Tabernero, C Montagut, D Azuara, R Dienstmann, R Salazar, A Vivancos
BACKGROUND: Circulating tumor DNA (ctDNA) is a potential source for tumor genome analysis. We explored the concordance between the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establish eligibility for anti-EGFR therapy. PATIENTS AND METHODS: A prospective-retrospective cohort study was performed. Tumor tissue from 146 mCRC patients was tested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumor tissue...
March 20, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28368335/recent-advances-in-targeting-the-egfr-signaling-pathway-for-the-treatment-of-metastatic-colorectal-cancer
#18
REVIEW
Yuji Miyamoto, Koichi Suyama, Hideo Baba
Outcomes for metastatic colorectal cancer (mCRC) patients have been improved by treatment with anti-epidermal growth factor receptor (anti-EGFR) antibodies, particularly when combined with predictive biomarkers to select patients lacking RAS mutations. New technologies such as liquid biopsy and next-generation sequencing have revealed that potential mechanisms of resistance to anti-EGFR therapies act through acquired mutations of KRAS and the EGFR ectodomain. Mutations in cross-talking molecular effectors that participate in downstream EGFR signaling are also negative predictors for anti-EGFR therapy...
April 2, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28366103/methods-of-selecting-combination-therapy-for-colorectal-cancer-patients-a-patent-evaluation-of-us20160025730a1
#19
Daniel Plano, Verónica Alcolea, Carmen Sanmartín, Arun K Sharma
Colorectal cancer (CRC) is the fourth most common cancer worldwide. Targeted therapy drugs (TTDs) are a valid treatment, epithelial growth factor receptor (EGFR) inhibitors being one of the most commonly used for CRC patients. However, this treatment is only useful for patients with wild-type KRAS (wtKRAS) and is effective only on about 40 to 60% of this subset due to the high plasticity of ErbB network. Areas covered: The invention proposes the use of ErbB protein levels and ErbB receptor dimer formation as biomarkers for selecting, predicting and monitoring CRC patients showing sensitivity to the action of EGFR inhibitors to benefit from the combination therapy of EGFR and HER2 inhibitors...
April 1, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28364379/micror-545-mediates-colorectal-cancer-cells-proliferation-through-up-regulating-epidermal-growth-factor-receptor-expression-in-hotair-long-non-coding-rna-dependent
#20
Xinli Huang, Sen Lu
The functional impact of recently discovered miRNAs in human cancer remains to be clarified. One miRNA in colorectal cancer which has attracted attention is miR-545. In this study, we examined the function of miR-545 in proliferation of colorectal cancer cells. Expressions of HOTAIR, miRNA-545, and epidermal growth factor receptor (EGFR) mRNA were measured in 100 paired cancerous and non-cancerous tissues as well as in SW480 and LOVO colorectal cancer cell (CRC) lines by quantitative RT-PCR. The relative protein level of EGFR was measured using western blotting...
March 31, 2017: Molecular and Cellular Biochemistry
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