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https://www.readbyqxmd.com/read/29679238/identification-of-subsets-of-actionable-genetic-alterations-in-kras-mutant-lung-cancers-using-association-rule-mining
#1
Junior Tayou
BACKGROUND: Lung cancer is the leading cause of cancer-related death in both men and women. KRAS mutations occur in ~ 25% of patients with lung cancer, and the presence of these mutations is associated with a poor prognosis. Unfortunately, efforts to directly target KRAS or its associated downstream MAPK or PI3K/AKT/mTOR pathways have seen little or no benefits. Here, I hypothesize that KRAS-mutant tumors do not respond to KRAS pathway therapies due to the co-occurrence of other activated cell survival pathways and/or mechanisms...
April 20, 2018: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/29675095/phase-i-ii-clinical-trial-of-everolimus-combined-with-gemcitabine-cisplatin-for-metastatic-triple-negative-breast-cancer
#2
In Hae Park, Sun-Young Kong, Youngmee Kwon, Min Kyeong Kim, Sung Hoon Sim, Jungnam Joo, Keun Seok Lee
Background: The PI3K/AKT/mTOR pathway is an important oncogenic driver in triple-negative breast cancer (TNBC). This study investigated the clinical efficacy and safety of the combination of gemcitabine and cisplatin with everolimus (GPE) in patients with metastatic TNBC. Methods: In phase I, we assessed the maximum tolerated dose (MTD) of GPE in metastatic TNBC patients. Then, using a seamless design, we conducted a randomized phase II trial to compare GPE to GP in terms of progression-free survival (PFS) and toxicity...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29674709/known-and-novel-roles-of-the-met-oncogene-in-cancer-a-coherent-approach-to-targeted-therapy
#3
REVIEW
Paolo M Comoglio, Livio Trusolino, Carla Boccaccio
The MET oncogene encodes an unconventional receptor tyrosine kinase with pleiotropic functions: it initiates and sustains neoplastic transformation when genetically altered ('oncogene addiction') and fosters cancer cell survival and tumour dissemination when transcriptionally activated in the context of an adaptive response to adverse microenvironmental conditions ('oncogene expedience'). Moreover, MET is an intrinsic modulator of the self-renewal and clonogenic ability of cancer stem cells ('oncogene inherence')...
April 19, 2018: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/29674595/developmental-and-oncogenic-programs-in-h3k27m-gliomas-dissected-by-single-cell-rna-seq
#4
Mariella G Filbin, Itay Tirosh, Volker Hovestadt, McKenzie L Shaw, Leah E Escalante, Nathan D Mathewson, Cyril Neftel, Nelli Frank, Kristine Pelton, Christine M Hebert, Christine Haberler, Keren Yizhak, Johannes Gojo, Kristof Egervari, Christopher Mount, Peter van Galen, Dennis M Bonal, Quang-De Nguyen, Alexander Beck, Claire Sinai, Thomas Czech, Christian Dorfer, Liliana Goumnerova, Cinzia Lavarino, Angel M Carcaboso, Jaume Mora, Ravindra Mylvaganam, Christina C Luo, Andreas Peyrl, Mara Popović, Amedeo Azizi, Tracy T Batchelor, Matthew P Frosch, Maria Martinez-Lage, Mark W Kieran, Pratiti Bandopadhayay, Rameen Beroukhim, Gerhard Fritsch, Gad Getz, Orit Rozenblatt-Rosen, Kai W Wucherpfennig, David N Louis, Michelle Monje, Irene Slavc, Keith L Ligon, Todd R Golub, Aviv Regev, Bradley E Bernstein, Mario L Suvà
Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority...
April 20, 2018: Science
https://www.readbyqxmd.com/read/29674500/novel-gpr34-and-ccr6-mutation-and-distinct-genetic-profiles-in-malt-lymphomas-of-different-sites
#5
Sarah Moody, Joe Sneath Thompson, Shih-Sung Chuang, Hongxiang Liu, Markus Raderer, George Vassiliou, Iwona Wlodarska, Fangtian Wu, Sergio Cogliatti, Alistair Robson, Margaret Ashton-Key, Yingwen Bi, John Goodlad, Ming-Qing Du
MALT lymphoma originates from a background of diverse chronic inflammatory disorders at various anatomic sites. The genetics underlying its development, particularly in those associated with autoimmune disorders, is poorly characterised. By whole exome sequencing of 21 cases of MALT lymphomas of the salivary gland and thyroid, we have identified recurrent somatic mutations in 2 G-protein coupled receptors (GPR34 and CCR6) not previously reported in human malignancies, 3 genes (PIK3CD, TET2, TNFRSF14) not previously implicated in MALT lymphoma, and a further 2 genes (TBL1XR1, NOTCH1) recently described in MALT lymphoma...
April 19, 2018: Haematologica
https://www.readbyqxmd.com/read/29673712/update-on-systemic-prostate-cancer-therapies-management-of-metastatic-castration-resistant-prostate-cancer-in-the-era-of-precision-oncology
#6
REVIEW
Philipp Nuhn, Johann S De Bono, Karim Fizazi, Stephen J Freedland, Maurizio Grilli, Philip W Kantoff, Guru Sonpavde, Cora N Sternberg, Srinivasan Yegnasubramanian, Emmanuel S Antonarakis
CONTEXT: Introduction of novel agents for the management of advanced prostate cancer provides a range of treatment options with notable benefits for men with metastatic castration-resistant prostate cancer (mCRPC). At the same time, understanding of optimal patient selection, effective sequential use, and development of resistance patterns remains incomplete. OBJECTIVE: To review current systemic therapies and recent advances in drug development for mCRPC and strategies to aid in patient selection and optimal sequencing...
April 16, 2018: European Urology
https://www.readbyqxmd.com/read/29672049/discovery-of-n-2-4-amino-cyclohexyl-9-cyclopentyl-n-6-4-morpholin-4-ylmethyl-phenyl-9-h-purine-2-6-diamine-as-a-potent-flt3-kinase-inhibitor-for-acute-myeloid-leukemia-with-flt3-mutations
#7
Tomas Gucky, Eva Řezníčková, Tereza Radosova Muchova, Radek Jorda, Zuzana Klejova, Veronika Malinkova, Karel Berka, Vaclav Bazgier, Haresh Ajani, Martin Lepsik, Vladimir Divoky, Vladimir Krystof
FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to standard cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivatives with potent FLT3 inhibitory activity. The lead compound 7d displays nanomolar activity in biochemical assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive...
April 19, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29671943/epithelial-to-mesenchymal-transition-in-the-context-of-epidermal-growth-factor-receptor-inhibition-in-non-small-cell-lung-cancer
#8
Giuseppe Bronte, Sara Bravaccini, Enrico Bronte, Marco Angelo Burgio, Christian Rolfo, Angelo Delmonte, Lucio Crinò
The identification of oncogenic driver mutations in non-small-cell lung cancer (NSCLC) has led to the development of targeted drugs. Tyrosine kinase inhibitors (TKIs) directed against the epidermal growth factor receptor (EGFR) target lung tumours bearing EGFR-activating mutations. This new therapeutic strategy has greatly improved tumour response rates. However, drug resistance invariably occurs during TKI-based treatment. Epithelial-to-mesenchymal transition (EMT) is one of the resistance mechanisms identified in EGFR-mutated NSCLC treated with TKIs...
April 19, 2018: Biological Reviews of the Cambridge Philosophical Society
https://www.readbyqxmd.com/read/29670173/overexpression-of-her2-in-the-pancreas-promotes-development-of-intraductal-papillary-mucinous-neoplasms-in-mice
#9
Wataru Shibata, Hiroto Kinoshita, Yohko Hikiba, Takeshi Sato, Yasuaki Ishii, Soichiro Sue, Makoto Sugimori, Nobumi Suzuki, Kosuke Sakitani, Hideaki Ijichi, Ryutaro Mori, Itaru Endo, Shin Maeda
Pancreatic ductal adenocarcinoma (PDA) has a 5-year survival rate of less than 5% and is the sixth leading cause of cancer death. Although KRAS mutations are one of the major driver mutations in PDA, KRAS mutation alone is not sufficient to induce invasive pancreatic cancer in mice model. HER2, also known as ERBB2, is a receptor tyrosine kinase, and overexpression of HER2 is associated with poor clinical outcomes in pancreatic cancer. However, no report has shown whether HER2 and its downstream signaling contributes to the pancreatic cancer development...
April 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29668342/sequencing-the-next-generation-of-glioblastomas
#10
Ivana Jovčevska
The most aggressive brain malignancy, glioblastoma, accounts for 60-70% of all gliomas and is uniformly fatal. According to the molecular signature, glioblastoma is divided into four subtypes (proneural, neural, classical, and mesenchymal), each with its own genetic background. The Cancer Genome Atlas project provides information about the most common genetic changes in glioblastoma. They involve mutations in TP53, TERT, and PTEN, and amplifications in EFGR, PDGFRA, CDK4, CDK6, MDM2, and MDM4. Recently, epigenetics was used to demonstrate the oncogenic roles of miR-124, miR-137, and miR-128...
April 18, 2018: Critical Reviews in Clinical Laboratory Sciences
https://www.readbyqxmd.com/read/29667105/the-role-of-autophagy-in-the-resistance-to-braf-inhibition-in-braf-mutated-melanoma
#11
Xiao Liu, Jinfeng Wu, Haihong Qin, Jinhua Xu
Malignant melanoma is the most aggressive and notorious skin cancer, and metastatic disease is associated with very poor long-term survival outcomes. Although metastatic melanoma patients with oncogenic mutations in the BRAF gene initially respond well to the treatment with specific BRAF inhibitors, most of them will eventually develop resistance to this targeted therapy. As a highly conserved catabolic process, autophagy is responsible for the maintenance of cellular homeostasis and cell survival, and is involved in multiple diseases, including cancer...
April 17, 2018: Targeted Oncology
https://www.readbyqxmd.com/read/29666622/chemotactic-cues-for-notch1-dependent-leukemia
#12
REVIEW
Erich Piovan, Valeria Tosello, Alberto Amadori, Paola Zanovello
The NOTCH signaling pathway is a conserved signaling cascade that regulates many aspects of development and homeostasis in multiple organ systems. Aberrant activity of this signaling pathway is linked to the initiation and progression of several hematological malignancies, exemplified by T-cell acute lymphoblastic leukemia (T-ALL). Interestingly, frequent non-mutational activation of NOTCH1 signaling has recently been demonstrated in B-cell chronic lymphocytic leukemia (B-CLL), significantly extending the pathogenic significance of this pathway in B-CLL...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29665843/next-generation-sequencing-analysis-of-receptor-type-tyrosine-kinase-genes-in-surgically-resected-colon-cancer-identification-of-gain-of-function-mutations-in-the-ret-proto-oncogene
#13
Duarte Mendes Oliveira, Katia Grillone, Chiara Mignogna, Valentina De Falco, Carmelo Laudanna, Flavia Biamonte, Rosa Locane, Francesco Corcione, Massimiliano Fabozzi, Rosario Sacco, Giuseppe Viglietto, Donatella Malanga, Antonia Rizzuto
BACKGROUND: Improvement in genetic characterization of Colon Cancer (CC) patients is required to propose new potential targets, since surgical resection coupled to chemotherapy, presents several limits such as cancer recurrence and drug resistance. Targeted therapies have more efficacy and less toxicity than standard treatments. One of the most relevant cancer-specific actionable targets are receptor tyrosine kinases (RTKs) whose role in CC need to be better investigated. METHODS: We have analysed 37 CC patients using the Ion AmpliSeq™ Comprehensive Cancer Panel (CCP)...
April 17, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29665313/refinement-of-the-endogenous-epitope-tagging-eet-technology-allows-the-identification-of-a-novel-nras-binding-partner-in-melanoma
#14
Michal Alon, Rafi Emmanuel, Nouar Qutob, Anna Bakhman, Victoria Peshti, Alexandra Brodezki, David Bassan, Mickey Kosloff, Yardena Samuels
The NRAS oncoprotein is highly mutated in melanoma. However, to date, no comprehensive proteomic study has been reported for NRAS. Here we utilized the Endogenous Epitope Tagging (EET) approach for the identification of novel NRAS binding partners. Using EET, an epitope tag is added to the endogenously expressed protein, via modification of its genomic coding sequence. Existing EET systems are not robust, suffer from high background and are labor-intensive. To this end, we present a polyadenylation signal-trap construct for N'-tagging, that generates a polycistronic mRNA with the gene of interest...
April 17, 2018: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29664013/%C3%AE-catenin-mediated-immune-evasion-pathway-frequently-operates-in-primary-cutaneous-melanomas
#15
Jérémie Nsengimana, Jon Laye, Anastasia Filia, Sally O'Shea, Sathya Muralidhar, Joanna Poźniak, Alastair Droop, May Chan, Christy Walker, Louise Parkinson, Joanne Gascoyne, Tracey Mell, Minttu Polso, Rosalyn Jewell, Juliette Randerson-Moor, Graham P Cook, D Timothy Bishop, Julia Newton-Bishop
Immunotherapy prolongs survival in only a subset of melanoma patients, highlighting the need to better understand the driver tumor microenvironment. We conducted bioinformatic analyses of 703 transcriptomes to probe the immune landscape of primary cutaneous melanomas in a population-ascertained cohort. We identified and validated 6 immunologically distinct subgroups, with the largest having the lowest immune scores and the poorest survival. This poor-prognosis subgroup exhibited expression profiles consistent with β-catenin-mediated failure to recruit CD141+ DCs...
April 16, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29663378/tyrosine-kinase-receptor-c-ros-oncogene-1-inhibition-alleviates-aberrant-bone-formation-of-twist-1-haploinsufficient-calvarial-cells-from-saethre-chotzen-syndrome-patients
#16
Esther Camp, Peter J Anderson, Andrew C W Zannettino, Carlotta A Glackin, Stan Gronthos
Saethre-Chotzen syndrome (SCS), associated with TWIST-1 mutations, is characterized by premature fusion of cranial sutures. TWIST-1 haploinsufficiency, leads to alterations in suture mesenchyme cellular gene expression patterns, resulting in aberrant osteogenesis and craniosynostosis. We analyzed the expression of the TWIST-1 target, Tyrosine kinase receptor c-ros-oncogene 1 (C-ROS-1) in TWIST-1 haploinsufficient calvarial cells derived from SCS patients and calvaria of Twist-1del/+ mutant mice and found it to be highly expressed when compared to TWIST-1 wild-type controls...
April 16, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29663340/molecular-signatures-in-hepatocellular-carcinoma-a-step-toward-rationally-designed-cancer-therapy
#17
REVIEW
Derek J Erstad, Bryan C Fuchs, Kenneth K Tanabe
Molecular characterization of hepatocellular carcinoma (HCC) has greatly improved our understanding of disease pathogenesis. Mutational analysis, RNA and microRNA expression profiling, and epigenetic characterization have revealed common aberrations in oncogenes and tumor suppressors that correlate with disease biology and serve as a guide for the rational design of targeted therapies. These approaches have also led to the discovery of novel targets, including mutations in isocitrate dehydrogenase and chromatin remodeling enzymes...
April 17, 2018: Cancer
https://www.readbyqxmd.com/read/29662640/potential-therapeutic-targets-of-tp53-gene-in-the-context-of-its-classically-canonical-functions-and-its-latest-non-canonical-functions-in-human-cancer
#18
REVIEW
Toshimichi Tanaka, Masahiko Watanabe, Keishi Yamashita
In normal tissue, p53 protein has a wide range of functions involving cell homeostasis; its mutation, however, permits a carcinogenic acquisition of function. TP53 gene mutation is a major genomic aberration in various human cancers and is a critical event in the multi-step carcinogenesis process. TP53 mutation is clinically relevant for the molecular classification of carcinogenesis, as most recently described rigorously by the Cancer Genome Atlas Research Network. TP53 gene mutation has been considered to work as a tumor suppressor gene through the loss of its transcriptional activity, which is designated as a canonical function...
March 23, 2018: Oncotarget
https://www.readbyqxmd.com/read/29660231/plakoglobin-restores-tumor-suppressor-activity-of-p53-r175h-mutant-by-sequestering-the-oncogenic-potential-of-%C3%AE-catenin
#19
Mahsa Alaee, Kristina Nool, Manijeh Pasdar
The tumor suppressor/transcription factor p53 is mutated in over 50% of all cancers. Some mutant p53 proteins not only have lost tumor suppressor activities but they also gain oncogenic functions (GOF). One of the most frequently expressed GOF p53 mutants is Arg175His (p53R175H ) with well-documented roles in cancer development and progression. Plakoglobin is a cell adhesion and signalling protein and a paralog of β-catenin. Unlike β-catenin that has oncogenic function via its role in Wnt pathway, plakoglobin generally acts as a tumor/metastasis suppressor...
April 16, 2018: Cancer Science
https://www.readbyqxmd.com/read/29659833/ift172-conditional-knockout-mice-exhibit-rapid-retinal-degeneration-and-protein-trafficking-defects
#20
Priya R Gupta, Nachiket Pendse, Scott H Greenwald, Mihoko Leon, Qin Liu, Eric A Pierce, Kinga M Bujakowska
Intraflagellar transport (IFT) is a bidirectional transport process that occurs along primary cilia and specialized sensory cilia, such as photoreceptor outer-segments. Genes coding for various IFT components are associated with ciliopathies. Mutations in IFT172 lead to diseases ranging from isolated retinal degeneration to severe syndromic ciliopathies. In this study, we created a mouse model of IFT172-associated retinal degeneration to investigate the ocular disease mechanism. We found that depletion of IFT172 in rod photoreceptors leads to a rapid degeneration of the retina, with severely reduced electroretinography responses by one month and complete outer-nuclear layer degeneration by two months...
April 5, 2018: Human Molecular Genetics
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