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Kras lung cancer

Tongtong Zhang, Junling Li
BACKGROUND: It has been proven that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and KRAS are common driver genes in non-small cell lung cancer (NSCLC). Molecular targeted therapy increases the overall response rate and progression-free survival (PFS) of patients with EGFR-sensitive mutation or echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion. However, target and targeted drugs for lung squamous cell carcinoma to indicate clinical therapy remain to be confirmed...
October 20, 2016: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Valentina Kovaleva, Anna-Lena Geissler, Lisa Lutz, Ralph Fritsch, Frank Makowiec, Sebastian Wiesemann, Ulrich T Hopt, Bernward Passlick, Martin Werner, Silke Lassmann
BACKGROUND: Targeted next generation sequencing (tNGS) has become part of molecular pathology diagnostics for determining RAS mutation status in colorectal cancer (CRC) patients as predictive tool for decision on EGFR-targeted therapy. Here, we investigated mutation profiles of case-matched tissue specimens throughout the disease course of CRC, to further specify RAS-status dynamics and to identify de novo mutations associated with distant metastases. METHODS: Case-matched formalin-fixed and paraffin-embedded (FFPE) resection specimens (n = 70; primary tumours, synchronous and/or metachronous liver and/or lung metastases) of 14 CRC cases were subjected to microdissection of normal colonic epithelial, primary and metastatic tumour cells, their DNA extraction and an adapted library protocol for limited DNA using the 48 gene TruSeq Amplicon Cancer Panel(TM), MiSeq sequencing and data analyses (Illumina)...
October 18, 2016: Molecular Cancer
Alessia Nottegar, Fabrizio Tabbò, Claudio Luchini, Matteo Brunelli, Emilio Bria, Nicola Veronese, Antonio Santo, Sara Cingarlini, Eliana Gilioli, Chiara Ogliosi, Albino Eccher, Licia Montagna, Serena Pedron, Claudio Doglioni, Maria G Cangi, Giorgio Inghirami, Marco Chilosi
Pulmonary adenocarcinoma with enteric differentiation (PAED) is a rare subtype of lung adenocarcinoma recently recognized in the WHO classification. It is defined as an adenocarcinoma in which the enteric component exceeds 50% and have to show the expression of at least 1 immunohistochemical marker of enteric differentiation. Although the definition of this tumor type is very important, above all in the differential diagnosis between a primary lung tumor and a metastasis of colorectal adenocarcinoma, this cancer still lacks a distinctive immunohistochemical and molecular signature...
October 7, 2016: Applied Immunohistochemistry & Molecular Morphology: AIMM
Ji-Youn Han, Jae-Jin Choi, Jin Young Kim, You Lim Han, Geon Kook Lee
No abstract text is available yet for this article.
October 17, 2016: BMC Cancer
Asha Bonney, Michael Christie, Anne Beaty, Sebastian Lunke, Graham Taylor, Louis Irving, Daniel Steinfort
BACKGROUND: With the rapid development of genotype-guided therapies, molecular testing is becoming important in the management of lung cancer. Bronchoscopy is one of the most common investigations performed to diagnose and investigate lung cancer. Given the limited samples often produced by bronchoscopy, this study aims to evaluate the feasibility of performing molecular testing on cell blocks created from bronchoscope cytology brush tip washings (BTW). METHODS: Patients with positive brush cytology for tumour cells had cell blocks created from the BTW...
September 2016: Journal of Thoracic Disease
Roz G Brant, Alan Sharpe, Tom Liptrot, Jonathan Dry, Elizabeth A Harrington, J Carl Barrett, Nicky Whalley, Chris Womack, Paul D Smith, Darren Hodgson
PURPOSE: To develop a clinically viable gene expression assay to measure RAS/RAF/MEK/ERK (RAS-ERK) pathway output suitable for hypothesis testing in non-small cell lung cancer (NSCLC) clinical studies. EXPERIMENTAL DESIGN: A published MEK-functional-activation signature (MEK signature) that measures RAS-ERK functional output was optimized for NSCLC in silico. NanoString assays were developed for the NSCLC optimized MEK signature and the 147-gene RAS signature. First, platform transfer from Affymetrix to NanoString, and signature modulation following treatment with KRAS siRNA and MEK inhibitor, were investigated in cell lines...
October 12, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Chih-Chieh Yu, Wanglong Qiu, Caroline S Juang, Mahesh M Mansukhani, Balazs Halmos, Gloria H Su
Mutant allele specific imbalance (MASI) was initially coined to describe copy number alterations associated with the mutant allele of an oncogene. The copy number gain (CNG) specific to the mutant allele can be readily observed in electropherograms. With the development of genome-wide analyses at base-pair resolution with copy number counts, we can now further differentiate MASI into those with CNG, with copy neutral alteration (also termed acquired uniparental disomy; UPD), or with loss of heterozygosity (LOH) due to the loss of the wild-type (WT) allele...
October 7, 2016: Cancer Letters
David G McFadden, Katerina Politi, Arjun Bhutkar, Frances K Chen, Xiaoling Song, Mono Pirun, Philip M Santiago, Caroline Kim-Kiselak, James T Platt, Emily Lee, Emily Hodges, Adam P Rosebrock, Roderick T Bronson, Nicholas D Socci, Gregory J Hannon, Tyler Jacks, Harold Varmus
Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene...
October 4, 2016: Proceedings of the National Academy of Sciences of the United States of America
Grit S Herter-Sprie, Shohei Koyama, Houari Korideck, Josephine Hai, Jiehui Deng, Yvonne Y Li, Kevin A Buczkowski, Aaron K Grant, Soumya Ullas, Kevin Rhee, Jillian D Cavanaugh, Neermala Poudel Neupane, Camilla L Christensen, Jan M Herter, G Mike Makrigiorgos, F Stephen Hodi, Gordon J Freeman, Glenn Dranoff, Peter S Hammerman, Alec C Kimmelman, Kwok-Kin Wong
Radiation therapy (RT), a critical modality in the treatment of lung cancer, induces direct tumor cell death and augments tumor-specific immunity. However, despite initial tumor control, most patients suffer from locoregional relapse and/or metastatic disease following RT. The use of immunotherapy in non-small-cell lung cancer (NSCLC) could potentially change this outcome by enhancing the effects of RT. Here, we report significant (up to 70% volume reduction of the target lesion) and durable (up to 12 weeks) tumor regressions in conditional Kras-driven genetically engineered mouse models (GEMMs) of NSCLC treated with radiotherapy and a programmed cell death 1 antibody (αPD-1)...
June 16, 2016: JCI Insight
Patrick H Lizotte, Elena V Ivanova, Mark M Awad, Robert E Jones, Lauren Keogh, Hongye Liu, Ruben Dries, Christina Almonte, Grit S Herter-Sprie, Abigail Santos, Nora B Feeney, Cloud P Paweletz, Meghana M Kulkarni, Adam J Bass, Anil K Rustgi, Guo-Cheng Yuan, Donald W Kufe, Pasi A Jänne, Peter S Hammerman, Lynette M Sholl, F Stephen Hodi, William G Richards, Raphael Bueno, Jessie M English, Mark A Bittinger, Kwok-Kin Wong
BACKGROUND. Immune checkpoint blockade improves survival in a subset of patients with non-small-cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited. METHODS. We performed comprehensive flow cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next-generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC)...
September 8, 2016: JCI Insight
Ying Zhou, Jason Dang, Kung-Yen Chang, Edwin Yau, Pedro Aza-Blanc, Jorge Moscat, Tariq M Rana
Global miRNA functional screens can offer a strategy to identify synthetic lethal interactions in cancer cells that might be exploited therapeutically. In this study, we applied this strategy to identify novel gene interactions in KRAS-mutant cancer cells. In this manner, we discovered miR-1298, a novel miRNA that inhibited the growth of KRAS-driven cells both in vitro and in vivo Using miR-TRAP affinity purification technology, we identified the tyrosine kinase FAK and the laminin subunit LAMB3 as functional targets of miR-1298...
October 1, 2016: Cancer Research
Stephen Sf Yip, John Kim, Thibaud Coroller, Chintan Parmar, Emmanuel Rios Velazquez, Elizabeth Huynh, Raymond Mak, Hugo Jwl Aerts
PURPOSE: Positron emission tomography (PET)-based radiomics has been used to non-invasively quantify the metabolic tumor phenotypes; however, little is known about the relationship between these phenotypes and underlying somatic mutations. This study assessed the association and predictive power of (18)F-FDG-PET-based radiomic features for somatic mutations in non-small cell lung cancer (NSCLC) patients. METHODS: 348 NSCLC patients underwent diagnostic (18)F-FDG-PET/CT scans and were tested for genetic mutations...
September 29, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
H Kadara, M Choi, J Zhang, E P Cuentas, J R Canales, S G Gaffney, Z Zhao, C Behrens, J Fujimoto, C Chow, Y Yoo, N Kalhor, C Moran, D Rimm, S Swisher, D L Gibbons, J Heymach, E Kaftan, J P Townsend, T J Lynch, J Schlessinger, J Lee, R P Lifton, I I Wistuba, R S Herbst
BACKGROUND: Lung adenocarcinomas (LUADs) lead to the majority of deaths attributable to lung cancer. We performed whole-exome sequencing (WES) and immune profiling analyses of a unique set of clinically annotated early-stage LUADs to better understand the pathogenesis of this disease and identify clinically relevant molecular markers. METHODS: We performed WES of 108 paired stage I-III LUADs and normal lung tissues using the Illumina HiSeq 2000 platform. Ten immune markers (PD-L1, PD-1, CD3, CD4, CD8, CD45ro, CD57, CD68, FOXP3 and Granzyme B) were profiled by imaging-based immunohistochemistry in a subset of LUADs (n=92)...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Shisuo Du, Virginia Lockamy, Lin Zhou, Christine Xue, Justin LeBlanc, Shonna Glenn, Gaurav Shukla, Yan Yu, Adam P Dicker, Dennis B Leeper, You Lu, Bo Lu
PURPOSE: To implement clinical stereotactic body radiation therapy (SBRT) using a small animal radiation research platform (SARRP) in a genetically engineered mouse model of lung cancer. METHODS AND MATERIALS: A murine model of multinodular Kras-driven spontaneous lung tumors was used for this study. High-resolution cone beam computed tomography (CBCT) imaging was used to identify and target peripheral tumor nodules, whereas off-target lung nodules in the contralateral lung were used as a nonirradiated control...
November 1, 2016: International Journal of Radiation Oncology, Biology, Physics
Jimi Kim, Elizabeth McMillan, Hyun Seok Kim, Niranjan Venkateswaran, Gurbani Makkar, Jaime Rodriguez-Canales, Pamela Villalobos, Jasper Edgar Neggers, Saurabh Mendiratta, Shuguang Wei, Yosef Landesman, William Senapedis, Erkan Baloglu, Chi-Wan B Chow, Robin E Frink, Boning Gao, Michael Roth, John D Minna, Dirk Daelemans, Ignacio I Wistuba, Bruce A Posner, Pier Paolo Scaglioni, Michael A White
The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies...
September 28, 2016: Nature
R H Mak, G Hermann, H Aerts, A B Chen, E H Baldini, D E Kozono, Y H Chen, P J Catalano, P Janne
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
Rémy Kinj, Pierre-Yves Bondiau, Eric François, Jean-Pierre Gérard, Arash O Naghavi, Axel Leysalle, Emmanuel Chamorey, Ludovic Evesque, Bernard Padovani, Antoine Ianessi, Karen Benezery, Jérôme Doyen
INTRODUCTION: Patients with metastatic colorectal cancer (CRC) may present with oligometastatic lung lesions for which stereotactic ablative radiotherapy (SABR) can be utilized. This study aims to report efficacy and prognostic factors associated with colorectal lung metastases treated with SABR. MATERIAL AND METHODS: This is a retrospective study including patients who presented with lung oligometastasis from CRC treated with SABR from September 2007 to November 2014...
August 31, 2016: Clinical Colorectal Cancer
E G Seviour, V Sehgal, D Mishra, R Rupaimoole, C Rodriguez-Aguayo, G Lopez-Berestein, J-S Lee, A K Sood, M P Kim, G B Mills, P T Ram
KRas is mutated in a significant number of human cancers and so there is an urgent therapeutic need to target KRas signalling. To target KRas in lung cancers we used a systems approach of integrating a genome-wide miRNA screen with patient-derived phospho-proteomic signatures of the KRas downstream pathway, and identified miR-193a-3p, which directly targets KRas. Unique aspects of miR-193a-3p biology include two functionally independent target sites in the KRas 3'UTR and clinically significant correlation between miR-193a-3p and KRas expression in patients...
September 26, 2016: Oncogene
Laura J Tafe, Kirsten J Pierce, Jason D Peterson, Francine de Abreu, Vincent A Memoli, Candice C Black, Jason R Pettus, Jonathan D Marotti, Edward J Gutmann, Xiaoying Liu, Keisuke Shirai, Konstantin H Dragnev, Christopher I Amos, Gregory J Tsongalis
Detection of somatic mutations in non-small cell lung cancers (NSCLCs), especially adenocarcinomas, is important for directing patient care when targeted therapy is available. Here, we present our experience with genotyping NSCLC using the Ion Torrent Personal Genome Machine (PGM) and the AmpliSeq Cancer Hotspot Panel v2. We tested 453 NSCLC samples from 407 individual patients using the 50 gene AmpliSeq Cancer Hotspot Panel v2 from May 2013 to July 2015. Using 10 ng of DNA, up to 11 samples were simultaneously sequenced on the Ion Torrent PGM (316 and 318 chips)...
September 2016: Neoplasia: An International Journal for Oncology Research
Robert U Svensson, Seth J Parker, Lillian J Eichner, Matthew J Kolar, Martina Wallace, Sonja N Brun, Portia S Lombardo, Jeanine L Van Nostrand, Amanda Hutchins, Lilliana Vera, Laurie Gerken, Jeremy Greenwood, Sathesh Bhat, Geraldine Harriman, William F Westlin, H James Harwood, Alan Saghatelian, Rosana Kapeller, Christian M Metallo, Reuben J Shaw
Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo...
October 2016: Nature Medicine
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