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Kinase targeting and clear cell carcinoma

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https://www.readbyqxmd.com/read/28984199/roles-of-alternative-splicing-in-modulating-transcriptional-regulation
#1
Jin Li, Yang Wang, Xi Rao, Yue Wang, Weixing Feng, Hong Liang, Yunlong Liu
BACKGROUND: The ability of a transcription factor to regulate its targets is modulated by a variety of genetic and epigenetic mechanisms. Alternative splicing can modulate gene function by adding or removing certain protein domains, and therefore affect the activity of protein. Reverse engineering of gene regulatory networks using gene expression profiles has proven valuable in dissecting the logical relationships among multiple proteins during the transcriptional regulation. However, it is unclear whether alternative splicing of certain proteins affects the activity of other transcription factors...
October 3, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/28978636/ezh2-modifies-sunitinib-resistance-in-renal-cell-carcinoma-by-kinome-reprogramming
#2
Remi Adelaiye-Ogala, Justin Budka, Nur P Damayanti, Justine Arrington, Mary W Ferris, Chuan-Chih Hsu, Sreenivasulu Chintala, Ashley R Orillion, Kiersten Marie Miles, Li Shen, May Elbanna, Eric Ciamporcero, Sreevani Arisa, Piergiorgio Pettazzoni, Giulio F Draetta, Mukund Seshadri, Bradley A Hancock, Milan Radovich, Janaiah Kota, Michael Buck, Heike Keilhack, Brian P McCarthy, Scott A Persohn, Paul R Territo, Yong Zang, Joseph Irudayaraj, Andy W Tao, Peter Hollenhorst, Roberto Pili
Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represent a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft (PDX) model that is intrinsically resistant to the RTKI sunitinib but not to the VEGF therapeutic antibody bevacizumab...
October 4, 2017: Cancer Research
https://www.readbyqxmd.com/read/28975890/identification-and-validation-of-novel-prognostic-markers-in-renal-cell-carcinoma
#3
Maj Rabjerg
Kidney cancer (Renal Cell Carcinoma (RCC)) is one of the most deadly malignancies due to frequent late diagnosis and poor treatment options. Histologically, RCC embraces a wide variety of different subtypes with the clear cell variant (ccRCC) being the most common, accounting for 75-90% of all RCCs. At present, the surveillance protocols for follow-up of RCC patients after radical nephrectomy are based on the American Joint Committee on Cancers (AJCC) pathological tumor-node-metastasis (TNM) classification system...
October 2017: Danish Medical Journal
https://www.readbyqxmd.com/read/28974261/the-150-most-important-questions-in-cancer-research-and-clinical-oncology-series-questions-57-66-edited-by-chinese-journal-of-cancer
#4
EDITORIAL
(no author information available yet)
Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which sparkle diverse thoughts, interesting communications, and potential collaborations among researchers all over the world. In this article, 10 more questions are presented as followed. Question 57. What are the major stresses that drive the formation, progression, and metastasis of a cancer? Question 58. What is the mechanism responsible for altering an acidic intracellular pH and a basic extracellular pH in normal tissue cells to a basic intracellular pH and an acidic extracellular pH in cancer cells, a fundamental and yet largely ignored phenomenon? Question 59...
October 3, 2017: Chinese Journal of Cancer
https://www.readbyqxmd.com/read/28952411/clinical-development-of-mtor-inhibitors-for-renal-cancer
#5
Michele Ghidini, Fausto Petrelli, Antonio Ghidini, Gianluca Tomasello, Jens Claus Hahne, Rodolfo Passalacqua, Sandro Barni
Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. In the last 10 years, clinical trials have established multitargeted tyrosine kinase inhibitors (TKIs) as the standard first-line treatment in patients with metastatic disease. Multiple agents are now available for treatment in subsequent lines.The mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus alone or with lenvatinib) are among the most effective options. Areas covered: This paper provides a complete and updated overview on mTOR inhibitors for the treatment of advanced RCC...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28951458/phgdh-as-a-key-enzyme-for-serine-biosynthesis-in-hif2%C3%AE-targeting-therapy-for-renal-cell-carcinoma
#6
Hirofumi Yoshino, Nijiro Nohata, Kazutaka Miyamoto, Masaya Yonemori, Takashi Sakaguchi, Satoshi Sugita, Toshihiko Itesako, Satoshi Kofuji, Masayuki Nakagawa, Rajvir Dahiya, Hideki Enokida
Continuous activation of hypoxia-inducible factor (HIF) is important for progression of renal cell carcinoma (RCC) and acquired resistance to anti-angiogenic multi-kinase and mTOR inhibitors. Recently, HIF2α antagonists PT2385 and PT2399 were developed and are being evaluated in a Phase I clinical trial for advanced or metastatic clear cell RCC (ccRCC). However, resistance to HIF2α antagonists would be expected to develop. In this study, we identified signals activated by HIF2α deficiency as candidate mediators of resistance to the multi-kinase inhibitor sunitinib...
September 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28947862/a-review-on-eph-ephrin-angiogenesis-and-lymphangiogenesis-in-gastric-colorectal-and-pancreatic-cancers
#7
Julia Rudno-Rudzińska, Wojciech Kielan, Ewelina Frejlich, Krzysztof Kotulski, Wojciech Hap, Krzysztof Kurnol, Przemysław Dzierżek, Marcin Zawadzki, Agnieszka Hałoń
Erythroprotein-producing human hepatocellular carcinoma receptors (Eph receptors) compose a subfamily of transmembrane protein-tyrosine kinases receptors that takes part in numerous physiological and pathological processes. Eph family receptor-interacting proteins (Ephrins) are ligands for those receptors. Eph/ephrin system is responsible for the cytoskeleton activity, cell adhesion, intercellular connection, cellular shape as well as cell motility. It affects neuron development and functioning, bone and glucose homeostasis, immune system and correct function of enterocytes...
August 2017: Chinese Journal of Cancer Research, Chung-kuo Yen Cheng Yen Chiu
https://www.readbyqxmd.com/read/28867195/simultaneous-targeting-pi3k-and-perk-pathways-promotes-cell-death-and-improves-the-clinical-prognosis-in-esophageal-squamous-carcinoma
#8
Shao-Qi Wang, Xiao Wang, Kai Zheng, Kai-Sheng Liu, Shao-Xiang Wang, Cong-Hua Xie
PI3K pathway is an important anti-tumor target, but its effect and mechanism is not clear in esophageal squamous cell carcinoma (ESCC). By analysis of the Cancer Genome Atlas (TCGA) datasets, we found that PI3Ks level were significantly upregulated in human esophageal cancer tissues compared with that in non-cancer tissues. The alteration of PI3K can significantly affect the overall patient survival in ESCC but not in esophageal adenocarcinoma (EAC). We found that the classic PI3K inhibitor LY294002 obviously inhibited the canonical mammalian target of rapamycin (mTOR) pathway and restrained the growth of ESCC with less toxicity to normal cells...
November 4, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28819401/identification-and-validation-of-soluble-carrier-family-expression-signature-for-predicting-poor-outcome-of-renal-cell-carcinoma
#9
Wan Fangning, Ma Chunguang, Zhang Hailiang, Shi Guohai, Zhu Yao, Dai Bo, Shen Yijun, Zhu Yiping, Ye Dingwei
The soluble carrier (SLC) family plays an important role in cell metabolism. The purpose of the current study was to screen SLCs as potential prognostic factors in clear cell renal cell carcinoma (ccRCC). A total of 509 patients with ccRCC from The Cancer Genome Atlas (TCGA) cohort were enrolled in this study. The expression profile of SLCs was obtained from the TCGA RNAseq database. Metadata of the TCGA cohort, including age, sex, TNM stage, tumor grade, American Joint Committee on Cancer stage, laterality, and overall survival, were collected...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28802060/taurine-upregulated-gene-1-functions-as-a-master-regulator-to-coordinate-glycolysis-and-metastasis-in-hepatocellular-carcinoma
#10
Yang-Hsiang Lin, Meng-Han Wu, Ya-Hui Huang, Chau-Ting Yeh, Mei-Ling Cheng, Hsiang-Cheng Chi, Chung-Ying Tsai, I-Hsiao Chung, Ching-Ying Chen, Kwang-Huei Lin
Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of Taurine upregulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion and glycolysis via suppression of miR-455-3p...
August 12, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28756136/addressing-the-best-treatment-for-non-clear-cell-renal-cell-carcinoma-a-meta-analysis-of-randomised-clinical-trials-comparing-vegfr-tkis-versus-mtori-targeted-therapies
#11
REVIEW
Chiara Ciccarese, Roberto Iacovelli, Matteo Brunelli, Francesco Massari, Davide Bimbatti, Emanuela Fantinel, Vincenzo De Marco, Antonio Benito Porcaro, Guido Martignoni, Walter Artibani, Giampaolo Tortora
AIM: Non-clear cell renal cell carcinoma (nccRCC) tumours include a heterogeneous group of malignancies that profoundly differ in terms of morphology, genetic profile, clinical behaviour and prognosis. The optimal treatment algorithm for nccRCC is still unknown and derived mainly from evidence available for ccRCC, being therefore represented by targeted agents against vascular endothelial growth factor and mammalian target of rapamycin (mTOR) pathways. We aimed to compare the efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKis) and mTOR inhibitors (mTORi) for the treatment of nccRCC patients...
September 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28728166/whole-genome-sequencing-revealed-novel-prognostic-biomarkers-and-promising-targets-for-therapy-of-ovarian-clear-cell-carcinoma
#12
Hiroaki Itamochi, Tetsuro Oishi, Nao Oumi, Satoshi Takeuchi, Kosuke Yoshihara, Mikio Mikami, Nobuo Yaegashi, Yasuhisa Terao, Kazuhiro Takehara, Kimio Ushijima, Hidemichi Watari, Daisuke Aoki, Tadashi Kimura, Toshiaki Nakamura, Yoshihito Yokoyama, Junzo Kigawa, Toru Sugiyama
BACKGROUND: Ovarian clear cell carcinoma (OCCC) is mostly resistant to standard chemotherapy that results in poor patient survival. To understand the genetic background of these tumours, we performed whole-genome sequencing of OCCC tumours. METHODS: Tumour tissue samples and matched blood samples were obtained from 55 Japanese women diagnosed with OCCC. Whole-genome sequencing was performed using the Illumina HiSeq platform according to standard protocols. RESULTS: Alterations to the switch/sucrose non-fermentable (SWI/SNF) subunit, the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway, and the receptor tyrosine kinase (RTK)/Ras signalling pathway were found in 51%, 42%, and 29% of OCCC tumours, respectively...
August 22, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28664385/pazopanib-a-review-in-advanced-renal-cell-carcinoma
#13
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...
August 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28652252/glycerol-3-phosphate-acyltransferase-1-promotes-tumor-cell-migration-and-poor-survival-in-ovarian-carcinoma
#14
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
#15
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...
October 19, 2017: Oncogene
https://www.readbyqxmd.com/read/28647567/stearoyl-coa-desaturase-regulates-sorafenib-resistance-via-modulation-of-er-stress-induced-differentiation
#16
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 regulating liver tumor-initiating cells (T-ICs) and sorafenib resistance, with the aim of developing 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
#17
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
#18
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
#19
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
#20
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
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