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Kinase targeting and clear cell carcinoma

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https://www.readbyqxmd.com/read/28664385/pazopanib-a-review-in-advanced-renal-cell-carcinoma
#1
REVIEW
James E Frampton
Pazopanib (Votrient®), an orally administered multi-targeted tyrosine kinase inhibitor that predominantly inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet-derived growth factor receptor-α and -β, and the stem cell factor receptor c-Kit, is approved in the EU, the USA and other countries for the treatment of advanced renal cell carcinoma (RCC). In randomized controlled trials in patients with advanced, predominantly clear-cell RCC, pazopanib significantly improved progression-free survival (PFS) compared with placebo in both treatment-naïve and cytokine-pretreated patients and, as a first-line therapy, was noninferior to intermittent sunitinib with respect to PFS...
June 29, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28652252/glycerol-3-phosphate-acyltransferase-1-promotes-tumor-cell-migration-and-poor-survival-in-ovarian-carcinoma
#2
Rosemarie Marchan, Bettina Büttner, Jörg Lambert, Karolina Edlund, Iris Glaeser, Meinolf Blaszkewicz, Gregor Leonhardt, Lisa Marienhoff, Darius Kaszta, Moritz Anft, Carsten Watzl, Katrin Madjar, Marianna Grinberg, Eugen Rempel, Roland Hergenröder, Silvia Selinski, Jörg Rahnenführer, Michaela S Lesjak, Joanna D Stewart, Cristina Cadenas, Jan G Hengstler
Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-α (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration...
June 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28650465/mcu-dependent-mitochondrial-ca-2-inhibits-nad-sirt3-sod2-pathway-to-promote-ros-production-and-metastasis-of-hcc-cells
#3
T Ren, H Zhang, J Wang, J Zhu, M Jin, Y Wu, X Guo, L Ji, Q Huang, H Zhang, H Yang, J Xing
Mitochondrial Ca(2+) signaling, which is strongly dependent on the mitochondrial Ca(2+) uniporter (MCU) complex, has a series of key roles in physiopathological processes, including energy metabolism, reactive oxygen species (ROS) production and cell apoptosis. However, a mechanistic understanding of how the mitochondrial Ca(2+) signaling is remodeled and its functional roles remains greatly limited in cancers, especially in hepatocellular carcinoma. Here we demonstrated that the MCU complex was dysregulated in hepatocellular carcinoma (HCC) cells and significantly correlated with metastasis and poor prognosis of HCC patients...
June 26, 2017: Oncogene
https://www.readbyqxmd.com/read/28647567/stearoyl-coa-desaturase-regulates-sorafenib-resistance-via-modulation-of-er-stress-induced-differentiation
#4
Mark Kin Fai Ma, Eunice Yuen Ting Lau, Doris Hoi Wing Leung, Jessica Lo, Nicole Pui Yu Ho, Lily Kwan Wai Cheng, Stephanie Ma, Chi Ho Lin, John A Copland, Jin Ding, Regina Cheuk Lam Lo, Irene Oi Lin Ng, Terence Kin Wah Lee
BACKGROUND & AIMS: We investigated the functional role and clinical significance of Stearoyl CoA desaturase-1 (SCD1) mediated endoplasmic reticulum (ER) stress in regulation of liver tumor-initiating cells (T-ICs) and sorafenib resistance, aiming to develop a novel therapeutic strategy against hepatocellular carcinomas (HCCs) METHODS: We evaluated the clinic-pathological relevance of SCD1 and its correlation with sorafenib resistance in large cohorts of HCC clinical samples by qPCR and immunohistochemical analyses...
June 22, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28632992/targeting-the-rhogtpase-rock-pathway-for-the-treatment-of-vhl-hif-pathway-driven-cancers
#5
Jordan M Thompson, Jaime Landman, Olga V Razorenova
The loss of the von Hippel-Lindau (VHL) tumor-suppressor is a major driver of Clear Cell Renal Cell Carcinoma (CC-RCC) resulting in the stabilization and overactivation of hypoxia inducible factors (HIFs). ROCK 1 is a well-known protein serine/threonine kinase which is recognized as having a role in cancer including alterations in cell motility, metastasis and angiogenesis. As a function of the later effect, we recently investigated and identified a synthetic lethal interaction between VHL loss and ROCK1 inhibition in CC-RCC that is dependent on HIF overactivation...
June 20, 2017: Small GTPases
https://www.readbyqxmd.com/read/28619630/hilar-fat-infiltration-a-new-prognostic-factor-in-metastatic-clear-cell-renal-cell-carcinoma-with-first-line-sunitinib-treatment
#6
Solène-Florence Kammerer-Jacquet, Angelique Brunot, Karim Bensalah, Boris Campillo-Gimenez, Mathilde Lefort, Sahar Bayat, Alain Ravaud, Frantz Dupuis, Mokrane Yacoub, Gregory Verhoest, Benoit Peyronnet, Romain Mathieu, Alexandra Lespagnol, Jean Mosser, Julien Edeline, Brigitte Laguerre, Jean-Christophe Bernhard, Nathalie Rioux-Leclercq
INTRODUCTION: The selection of patients with metastatic clear cell renal cell carcinoma (ccRCC) who may benefit from targeted tyrosine kinase inhibitors has been a challenge, even more so now with the advent of new therapies. Hilar fat infiltration (HFI) is a validated prognostic factor in nonmetastatic ccRCC (TNM 2009 staging system) but has never been studied in metastatic patients. We aimed to assess its phenotype and prognostic effect in patients with metastatic ccRCC treated with first-line sunitinib...
June 12, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28599476/identification-of-gene-markers-associated-with-metastasis-in-clear-cell-renal-cell-carcinoma
#7
Hailing Yang, Pengfei Huo, Guozhang Hu, Bo Wei, Dalian Kong, Hongjun Li
The present study aimed to screen potential target genes for the early diagnosis and treatment of early metastatic clear cell renal cell carcinoma (ccRCC) using the microarray data of early metastatic and non-metastatic ccRCC samples. The DNA microarray dataset GSE47352 was downloaded from Gene Expression Omnibus and included 4 early metastatic and 5 non-metastatic ccRCC samples. Differentially expressed genes (DEGs) were screened using the limma package. Then, pheatmap package was used to conduct two-way clustering for the DEGs...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28598822/patient-specific-molecular-alterations-are-associated-with-metastatic-clear-cell-renal-cell-cancer-progressing-under-tyrosine-kinase-inhibitor-therapy
#8
Steffen Dietz, Holger Sültmann, YueJun Du, Eva Reisinger, Anja Lisa Riediger, Anna-Lena Volckmar, Albrecht Stenzinger, Matthias Schlesner, Dirk Jäger, Markus Hohenfellner, Stefan Duensing, Carsten Grüllich, Sascha Pahernik
The availability of tyrosine kinase inhibitors (TKI) during the past ten years has led to improved response and overall survival of patients suffering from metastatic clear cell renal cell carcinoma (ccRCC). However, most of these tumors will eventually progress due to resistance evolving under therapy. The objective of this pilot study was to determine whether molecular alterations in ccRCC tissues sampled over the course of the disease might be suggestive of potential therapies. We performed whole exome sequencing of nine samples from four patients in the MORE (Molecular Renal Cancer Evolution) trial...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28561652/evolving-treatment-paradigm-in-metastatic-renal-cell-carcinoma
#9
David M Gill, Neeraj Agarwal, Ulka Vaishampayan
The treatment paradigm for advanced and metastatic renal cell carcinoma (mRCC) has evolved rapidly since the arrival of targeted therapies and novel immunotherapies. mRCC was previously treated only with cytokines. However, discoveries of mutations affecting the von Hippel-Lindau tumor suppressor gene (leading to increased expression of VEGF and hypoxia inducible factor/HIF-1) and of deregulations in the phosphatidylinositol-3 kinase/AKT/mTOR pathway (resulting in tumor angiogenesis, cell proliferation, and tumor growth) have led to the development of numerous targeted therapies...
2017: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/28550387/correlation-of-c-met-expression-with-pd-l1-expression-in-metastatic-clear-cell-renal-cell-carcinoma-treated-by-sunitinib-first-line-therapy
#10
Solène-Florence Kammerer-Jacquet, Sarah Medane, Karim Bensalah, Jean-Christophe Bernhard, Mokrane Yacoub, Frantz Dupuis, Alain Ravaud, Grégory Verhoest, Romain Mathieu, Benoit Peyronnet, Angélique Brunot, Brigitte Laguerre, Alexandra Lespagnol, Jean Mosser, Frédéric Dugay, Marc-Antoine Belaud-Rotureau, Nathalie Rioux-Leclercq
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is highly metastatic. Cabozantinib, an anti-angiogenic tyrosine kinase inhibitor that targets c-MET, provided interesting results in metastatic ccRCC treatment. OBJECTIVE: To understand better the role of c-MET in ccRCC, we assessed its status in a population of patients with metastatic ccRCC. PATIENTS AND METHODS: For this purpose, tumor samples were analyzed for c-MET expression by immunohistochemistry (IHC), for c-MET copy number alterations by fluorescence in situ hybridization (FISH), and for c-MET mutations by next generation sequencing (NGS) in a retrospective cohort of 90 primary ccRCC of patients with metastases treated by first-line sunitinib...
May 26, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28454214/genome-wide-analysis-of-gynecologic-cancer-the-cancer-genome-atlas-in-ovarian-and-endometrial-cancer
#11
Moito Iijima, Kouji Banno, Ryuichiro Okawa, Megumi Yanokura, Miho Iida, Takashi Takeda, Haruko Kunitomi-Irie, Masataka Adachi, Kanako Nakamura, Kiyoko Umene, Yuya Nogami, Kenta Masuda, Eiichiro Tominaga, Daisuke Aoki
Cancer typically develops due to genetic abnormalities, but a single gene abnormality cannot completely account for the onset of cancer. The Cancer Genome Atlas (CGA) project was conducted for the cross-sectional genome-wide analysis of numerous genetic abnormalities in various types of cancer. This approach has facilitated the identification of novel AT-rich interaction domain 1A gene mutations in ovarian clear cell carcinoma, frequent tumor protein 53 (TP53) gene mutations in high-grade ovarian serous carcinoma, and Kirsten rat sarcoma and B-rapidly accelerated fibrosarcoma proto-oncogene, serine/threonine kinase gene mutations in low-grade ovarian serous carcinoma...
March 2017: Oncology Letters
https://www.readbyqxmd.com/read/28435529/-18-f-labeled-pyrido-3-4-d-pyrimidine-as-an-effective-probe-for-imaging-of-l858r-mutant-epidermal-growth-factor-receptor
#12
Hiroyuki Kimura, Haruka Okuda, Masumi Ishiguro, Kenji Arimitsu, Akira Makino, Ryuichi Nishii, Anna Miyazaki, Yusuke Yagi, Hiroyuki Watanabe, Ikuo Kawasaki, Masahiro Ono, Hideo Saji
In nonsmall-cell lung carcinoma patients, L858R mutation of epidermal growth factor receptor (EGFR) is often found, and molecular target therapy using EGFR tyrosine kinase inhibitors is effective for the patients. However, the treatment frequently develops drug resistance by secondary mutation, of which approximately 50% is T790M mutation. Therefore, the ability to predict whether EGFR will undergo secondary mutation is extremely important. We synthesized a novel radiofluorinated 4-(anilino)pyrido[3,4-d]pyrimidine derivative ([(18)F]APP-1) and evaluated its potential as a positron emission tomography (PET) imaging probe to discriminate the difference in mutations of tumors...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28433634/dual-sphingosine-kinase-inhibitor-ski-ii-enhances-sensitivity-to-5-fluorouracil-in-hepatocellular-carcinoma-cells-via-suppression-of-osteopontin-and-fak-igf-1r-signalling
#13
Petra Grbčić, Ivana Tomljanović, Marko Klobučar, Sandra Kraljević Pavelić, Ksenija Lučin, Mirela Sedić
Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related deaths globally. Although 5-Fluorouracil (5-FU) is used as the first choice treatment for advanced HCC, it exerts poor efficacy and is associated with acquired and intrinsic resistance. Sphingosine kinases (Sphk) 1 and 2 play tumour-promoting roles in different cancer types including HCC and thus represent promising pharmacological targets. In the present study, we have investigated for the first time the anticancer efficacy and underlying molecular mechanisms of combined administration of 5-FU and dual Sphk1/Sphk2 inhibitor SKI-II (4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]phenol) in HepG2 hepatocellular carcinoma cells...
June 10, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28418903/kinomic-profiling-identifies-focal-adhesion-kinase-1-as-a-therapeutic-target-in-advanced-clear-cell-renal-cell-carcinoma
#14
Arindam P Ghosh, Christopher D Willey, Joshua C Anderson, Karim Welaya, Dongquan Chen, Amitkumar Mehta, Pooja Ghatalia, Ankit Madan, Gurudatta Naik, Sunil Sudarshan, Guru Sonpavde
The introduction of targeted therapies has caused a paradigm shift in the treatment of metastatic clear cell (cc)-renal cell carcinoma (RCC). We hypothesized that determining differential kinase activity between primary and metastatic tumor sites may identify critical drivers of progression and relevant therapeutic targets in metastatic disease. Kinomic profiling was performed on primary tumor and metastatic tumor deposits utilizing a peptide substrate microarray to detect relative tyrosine phosphorylation activity...
April 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28347229/high-expression-of-g-protein-signaling-modulator-2-in-hepatocellular-carcinoma-facilitates-tumor-growth-and-metastasis-by-activating-the-pi3k-akt-signaling-pathway
#15
Xiao-Qin He, Yue-Feng Zhang, Jia-Jun Yu, Yuan-Yuan Gan, Na-Na Han, Mei-Xia Zhang, Wei Ge, Jun-Jian Deng, Yong-Fa Zheng, Xi-Ming Xu
The aim of this study was to investigate the role of G-protein signaling modulator 2 in the carcinogenesis and progression of hepatocellular carcinoma. We previously showed that G-protein signaling modulator 2 was upregulated in hepatitis B virus-related hepatocellular carcinoma tissues through a hierarchical clustering analysis. With this study, we first assessed the expression pattern of G-protein signaling modulator 2 in hepatocellular carcinoma specimens and adjacent noncancerous tissues; clinical data were analyzed, along survival times, utilizing the Kaplan-Meier method...
March 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28337374/polypyrimidine-tract-binding-protein-1-promotes-proliferation-migration-and-invasion-in-clear-cell-renal-cell-carcinoma-by-regulating-alternative-splicing-of-pkm
#16
Junyi Jiang, Xu Chen, Hao Liu, Jing Shao, Ruihui Xie, Peng Gu, Chaohui Duan
Polypyrimidine Tract-Binding Protein 1 (PTBP1) is an essential RNA-binding protein that regulates diverse biological events through regulating alternative splice of mRNA. PTBP1 induces cancer-promoting splice variants and is related to tumorigenesis in several cancers. However, both the expression patterns and biological mechanisms of PTBP1 in clear-cell renal cell carcinoma (ccRCC) are unclear. We investigated PTBP1 expression in 533 ccRCC patients from TCGA and 30 ccRCC patients by immunohistochemistry, and found that PTBP1 expression levels were significantly increased in ccRCC tissues and that high PTBP1 expression was closely correlated with advanced tumor stage, AJCC stage and poor prognosis...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28327152/trim8-restores-p53-tumour-suppressor-function-by-blunting-n-myc-activity-in-chemo-resistant-tumours
#17
Francesca Mastropasqua, Flaviana Marzano, Alessio Valletti, Italia Aiello, Giuseppe Di Tullio, Annalisa Morgano, Sabino Liuni, Elena Ranieri, Luisa Guerrini, Giuseppe Gasparre, Elisabetta Sbisà, Graziano Pesole, Antonio Moschetta, Mariano Francesco Caratozzolo, Apollonia Tullo
BACKGROUND: TRIM8 plays a key role in controlling the p53 molecular switch that sustains the transcriptional activation of cell cycle arrest genes and response to chemotherapeutic drugs. The mechanisms that regulate TRIM8, especially in cancers like clear cell Renal Cell Carcinoma (ccRCC) and colorectal cancer (CRC) where it is low expressed, are still unknown. However, recent studies suggest the potential involvement of some microRNAs belonging to miR-17-92 and its paralogous clusters, which could include TRIM8 in a more complex pathway...
March 21, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28325666/development-of-novel-patient-derived-preclinical-models-from-malignant-effusions-in-patients-with-tyrosine-kinase-inhibitor-resistant-clear-cell-renal-cell-carcinoma
#18
Jiryeon Jang, Oliver Rath, Julia Schueler, Hyun Hwan Sung, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Moo Lee, Han-Yong Choi, Ghee-Young Kwon, Woong Yang Park, Jeeyun Lee, Se Hoon Park
PURPOSE: Although targeting angiogenesis with tyrosine kinase inhibitors (TKIs) has become standard of care in the treatment of clear cell renal cell carcinoma (RCC), resistance mechanism are not fully understood, and there is a need to develop new therapeutic options overcoming them. METHODS AND MATERIALS: To develop a preclinical model that predicts clinical activity of novel agents in 19 RCC patients, we established patient-derived cell (PDC) and xenograft (PDX) models derived from malignant effusions or surgical specimen...
June 2017: Translational Oncology
https://www.readbyqxmd.com/read/28259988/targeting-glutamine-metabolism-and-the-focal-adhesion-kinase-additively-inhibits-the-mammalian-target-of-the-rapamycin-pathway-in-spheroid-cancer-stem-like-properties-of-ovarian-clear-cell-carcinoma-in%C3%A2-vitro
#19
Masakazu Sato, Kei Kawana, Katsuyuki Adachi, Asaha Fujimoto, Mitsuyo Yoshida, Hiroe Nakamura, Haruka Nishida, Tomoko Inoue, Ayumi Taguchi, Juri Ogishima, Satoko Eguchi, Aki Yamashita, Kensuke Tomio, Osamu Wada-Hiraike, Katsutoshi Oda, Takeshi Nagamatsu, Yutaka Osuga, Tomoyuki Fujii
Ovarian cancer is one of the leading causes of death in the world, which is linked to its resistance to chemotherapy. Strategies to overcome chemoresistance have been keenly investigated. Culturing cancer cells in suspension, which results in formation of spheroids, is a more accurate reflection of clinical cancer behavior in vitro than conventional adherent cultures. By performing RNA-seq analysis, we found that the focal adhesion pathway was essential in spheroids. The phosphorylation of focal adhesion kinase (FAK) was increased in spheroids compared to adherent cells, and inhibition of FAK in spheroids resulted in inhibition of the downstream mammalian target of the rapamycin (mTOR) pathway in ovarian clear cell carcinomas...
April 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28215740/inhibition-of-htert-expression-by-map-kinase-inhibitor-induces-cell-death-in-renal-cell-carcinoma
#20
Deeksha Pal, Ujjawal Sharma, Shrawan Kumar Singh, Nandita Kakkar, Rajendra Prasad
BACKGROUND: Human telomerase reverse transcriptase (hTERT) is one of the components of telomerase enzyme and its activity is associated with cell proliferation and differentiation. Extracellular signal regulated kinase (ERK)-mitogen activated protein kinase signaling pathway play an important role in hTERT expression. The present study was conducted to ascertain hTERT messenger RNA (mRNA) expression in renal cell carcinoma (RCC) and its association with clinicopathological characteristics...
June 2017: Urologic Oncology
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