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https://www.readbyqxmd.com/read/28806782/the-use-of-18f-fluoro-deoxy-glucose-positron-emission-tomography-18f-fdg-pet-as-a-non-invasive-pharmacodynamic-biomarker-to-determine-the-minimally-pharmacologically-active-dose-of-azd8835-a-novel-pi3k%C3%AE-inhibitor
#1
Juliana Maynard, Sally-Ann Emmas, Francois-Xavier Ble, Herve Barjat, Emily Lawrie, Urs Hancox, Urszula M Polanska, Alison Pritchard, Kevin Hudson
BACKGROUND: The phosphatidyl inositol 3 kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) signal transduction pathway is frequently de-regulated and activated in human cancer and is an important therapeutic target. AZD8835 is a PI3K inhibitor, with selectivity against PI3K α and δ isoforms, which is currently in Phase 1 clinical trials. 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) is a non-invasive pharmacodynamic imaging biomarker that has become an integral part of drug development...
2017: PloS One
https://www.readbyqxmd.com/read/28806393/craf-gene-fusions-in-pediatric-low-grade-gliomas-define-a-distinct-drug-response-based-on-dimerization-profiles
#2
P Jain, T M Fierst, H J Han, T E Smith, A Vakil, P J Storm, A C Resnick, A J Waanders
Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways...
August 14, 2017: Oncogene
https://www.readbyqxmd.com/read/28804691/combination-of-celecoxib-celebrex-%C3%A2-and-cd19-car-redirected-ctl-immunotherapy-for-the-treatment-of-b-cell-non-hodgkin-s-lymphomas
#3
REVIEW
Tam Nm Dinh, Alexandra S Onea, Ali R Jazirehi
The nonsteroidal anti-inflammatory drug (NSAID) Celecoxib (Celebrex(®)) received Food and Drug Administration (FDA) approval in 1998 for treatment of osteoarthritis and rheumatoid arthritis, and in recent years, its use has been extended to various types of malignancies, such as breast, colon, and urinary cancers. To maintain the survival of malignant B cells, non-Hodgkin's Lymphoma (NHL) is highly dependent on inflammatory microenvironment, and is inhibited by celecoxib. Celecoxib hinders tumor growth interacting with various apoptotic genes, such as cyclooxygenase-2 (Cox-2), B-cell lymphoma 2 (Bcl-2) family, phosphor-inositide-3 kinase/serine-threonine-specific protein kinase (PI3K/Akt), and inhibitors of apoptosis proteins (IAP) family...
2017: American Journal of Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28803243/lithium-sensitivity-of-store-operated-ca2-entry-and-survival-of-fibroblasts-isolated-from-chorea-acanthocytosis-patients
#4
Lisann Pelzl, Bhaeldin Elsir, Itishri Sahu, Rosi Bissinger, Yogesh Singh, Basma Sukkar, Sabina Honisch, Ludger Schoels, Mohamed Jemaà, Elisabeth Lang, Alexander Storch, Andreas Hermann, Christos Stournaras, Florian Lang
BACKGROUND: The widely expressed protein chorein fosters activation of the phosphoinositide 3 kinase (PI3K) pathway thus supporting cell survival. Loss of function mutations of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) causes chorea-acanthocytosis (ChAc), a neurodegenerative disorder paralleled by deformations of erythrocytes. In mice, genetic knockout of chorein leads to enhanced neuronal apoptosis. PI3K dependent signalling upregulates Orai1, a pore forming channel protein accomplishing store operated Ca2+ entry (SOCE)...
August 11, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28802037/the-pi3k-pathway-in-human-disease
#5
REVIEW
David A Fruman, Honyin Chiu, Benjamin D Hopkins, Shubha Bagrodia, Lewis C Cantley, Robert T Abraham
Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28801451/adult-high-grade-b-cell-lymphoma-with-burkitt-lymphoma-signature-genomic-features-and-potential-therapeutic-targets
#6
Alyssa Bouska, Chengfeng Bi, Waseem Lone, Weiwei Zhang, Ambreen Kedwaii, Tayla Heavican, Cynthia M Lachel, Jiayu Yu, Roberto Ferro, Nanees Eldorghamy, Timothy C Greiner, Julie Vose, Dennis D Weisenburger, Randy D Gascoyne, Andreas Rosenwald, German Ott, Elias Campo, Lisa M Rimsza, Elaine S Jaffe, Rita M Braziel, Reiner Siebert, Rodney R Miles, Sandeep Dave, Anupama Reddy, Jan Delabie, Louis M Staudt, Joo Y Song, Timothy W McKeithan, Kai Fu, Michael Green, Wing C Chan, Javeed Iqbal
The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene-signature (adult-mBL), revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24 and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes...
August 11, 2017: Blood
https://www.readbyqxmd.com/read/28800861/ipatasertib-plus-paclitaxel-versus-placebo-plus-paclitaxel-as-first-line-therapy-for-metastatic-triple-negative-breast-cancer-lotus-a-multicentre-randomised-double-blind-placebo-controlled-phase-2-trial
#7
Sung-Bae Kim, Rebecca Dent, Seock-Ah Im, Marc Espié, Sibel Blau, Antoinette R Tan, Steven J Isakoff, Mafalda Oliveira, Cristina Saura, Matthew J Wongchenko, Amy V Kapp, Wai Y Chan, Stina M Singel, Daniel J Maslyar, José Baselga
BACKGROUND: The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer. METHODS: In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium...
August 8, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28800461/design-synthesis-and-biological-evaluation-of-novel-3-substituted-imidazo-1-2-a-pyridine-and-quinazolin-4-3h-one-derivatives-as-pi3k%C3%AE-inhibitors
#8
Yan-Hua Fan, Wei Li, Dan-Dan Liu, Meng-Xuan Bai, Hong-Rui Song, Yong-Nan Xu, SangKook Lee, Zhi-Peng Zhou, Jian Wang, Huai-Wei Ding
Phosphatidylinositol 3-kinase (PI3K) is a pivotal regulator of intracellular signaling pathways and considered as a promising target in the development of a therapeutic treatment of cancer. Among the different PI3K subtypes, the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in majority of human cancers. Therefore, the inhibition of PI3Kα has been considered to be an efficient approach for the treatment of cancer. In this study, two series compounds containing hydrophilic group in imidazo[1,2-a]pyridine and quinazolin-4(3H)-one were synthesized and their antiproliferative activities against five cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638 and A549, were evaluated...
August 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28800359/the-selective-pi3k%C3%AE-inhibitor-byl719-as-a-novel-therapeutic-option-for-neuroendocrine-tumors-results-from-multiple-cell-line-models
#9
Svenja Nölting, Jakob Rentsch, Helma Freitag, Katharina Detjen, Franziska Briest, Markus Möbs, Victoria Weissmann, Britta Siegmund, Christoph J Auernhammer, Elke Tatjana Aristizabal Prada, Michael Lauseker, Ashley Grossman, Samantha Exner, Christian Fischer, Carsten Grötzinger, Jörg Schrader, Patricia Grabowski
BACKGROUND/AIMS: The therapeutic options for metastatic neuroendocrine tumors (NETs) are limited. As PI3K signaling is often activated in NETs, we have assessed the effects of selective PI3Kp110α inhibition by the novel agent BYL719 on cell viability, colony formation, apoptosis, cell cycle, signaling pathways, differentiation and secretion in pancreatic (BON-1, QGP-1) and pulmonary (H727) NET cell lines. METHODS: Cell viability was investigated by WST-1 assay, colony formation by clonogenic assay, apoptosis by caspase3/7 assay, the cell cycle by FACS, cell signaling by Western blot analysis, expression of chromogranin A and somatostatin receptors 1/2/5 by RT-qPCR, and chromogranin A secretion by ELISA...
2017: PloS One
https://www.readbyqxmd.com/read/28798270/a-phase-i-dose-escalation-study-of-the-safety-and-pharmacokinetics-of-pictilisib-in-combination-with-erlotinib-in-patients-with-advanced-solid-tumors
#10
Stephen Leong, Rebecca A Moss, Daniel W Bowles, Joseph A Ware, Jing Zhou, Jill M Spoerke, Mark R Lackner, Geetha Shankar, Jennifer L Schutzman, Ruud van der Noll, Emile E Voest, Jan H M Schellens
BACKGROUND: Epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K) are involved in the proliferation and survival of many cancer types. Enhanced antitumor activity may be achieved through combined inhibition of these pathways. We report results for pictilisib (GDC-0941, a class I pan-PI3K inhibitor) plus erlotinib (an EGFR tyrosine kinase inhibitor) in patients with advanced solid tumors. MATERIALS AND METHODS: A 3 + 3 dose-escalation study was carried out at a starting daily dose of 60 mg pictilisib on days 1-21 of a 28-day cycle and 150 mg erlotinib from day 2 of cycle 1...
August 10, 2017: Oncologist
https://www.readbyqxmd.com/read/28798142/accumulation-of-smooth-muscle-22%C3%AE-protein-accelerates-senescence-of-vascular-smooth-muscle-cells-via-stabilization-of-p53-in-vitro-and-in-vivo
#11
Sui-Bing Miao, Xiao-Li Xie, Ya-Juan Yin, Li-Li Zhao, Fan Zhang, Ya-Nan Shu, Rong Chen, Peng Chen, Li-Hua Dong, Yan-Ling Lin, Pin Lv, Dan-Dan Zhang, Xi Nie, Zhen-Ying Xue, Mei Han
OBJECTIVE: Smooth muscle (SM) 22α, an actin-binding protein, displays an upregulated expression as a marker during cellular senescence. However, the causal relationship between SM22α and senescence is poorly understood. This study aimed to investigate the role of SM22α in angiotensin II (Ang II)-induced senescence of vascular smooth muscle cells (VSMCs). APPROACH AND RESULTS: We prepared a model of VSMC senescence induced by Ang II and found that the expression of SM22α in VSMCs was increased in response to chronic Ang II treatment...
August 10, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28797845/the-hsp90-inhibitor-nvp-auy922-attenuates-intrinsic-pi3k-inhibitor-resistance-in-kras-mutant-non-small-cell-lung-cancer
#12
Kang-Seo Park, Hannah Yang, Junyoung Choi, Seyoung Seo, Deokhoon Kim, Chang Hoon Lee, Hanwool Jeon, Sang-We Kim, Dae Ho Lee
More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway...
August 7, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28796798/hspb5-correlates-with-poor-prognosis-in-colorectal-cancer-and-prompts-epithelial-mesenchymal-transition-through-erk-signaling
#13
Qinghua Li, Yanlan Wang, Yuexing Lai, Ping Xu, Zhiwen Yang
Alpha B-crystallin (HspB5) is abnormally expressed in tumor tissues and portends a poor prognosis in cancer patients. However, the role of HspB5 in colorectal cancer (CRC) is still unclear. Seventy CRC patients and 40 healthy volunteers were sampled from August 2012 to March 2015 in order to determine the clinical significance of HspB5. In vitro cellular studies were used to validate its molecular mechanisms in CRC. Our clinical data indicated that HspB5 was up-regulated, and had a positive association with TNM stage CRC patients...
2017: PloS One
https://www.readbyqxmd.com/read/28796787/the-quinic-acid-derivative-kz-41-prevents-glucose-induced-caspase-3-activation-in-retinal-endothelial-cells-through-an-igf-1-receptor-dependent-mechanism
#14
Hui He, Rebecca L Weir, Jordan J Toutounchian, Jayaprakash Pagadala, Jena J Steinle, Jerome Baudry, Duane D Miller, Charles R Yates
Retinal microaneurysms, an early disease manifestation of diabetic retinopathy, are associated with retinal endothelial cell (REC) death and macular edema. We previously demonstrated that a quinic acid (QA) analog, KZ-41, promoted REC survival by blunting stress-induced p38 MAPK activation. Herein, we sought to expand our understanding of the pro-survival signal transduction pathways actuated by KZ-41. Using human RECs exposed to high glucose (25 mM, 72 hours), we demonstrated that KZ-41 blocks caspase-3 activation by triggering phosphorylation of the PI3K regulatory subunit (p85; Tyr458) and its downstream target Akt (Ser473)...
2017: PloS One
https://www.readbyqxmd.com/read/28796257/lncrna-oip5-as1-loss-induced-microrna-410-accumulation-regulates-cell-proliferation-and-apoptosis-by-targeting-klf10-via-activating-pten-pi3k-akt-pathway-in-multiple-myeloma
#15
Nan Yang, Jinqiu Chen, Hui Zhang, Xiaman Wang, Huan Yao, Yue Peng, Wanggang Zhang
Numerous studies confirmed that aberrant miRNAs expression contributes to multiple myeloma (MM) development and progression. However, the roles of specific miRNAs in MM remain to be investigated. In present study, we demonstrated that miR-410 expression was increased in MM newly diagnosed and relapsed tissues and cell lines. Clinical analysis revealed that miR-410 was positively correlated with advanced ISS stage. Moreover, high miR-410 expression in MM patients showed an obvious shorter overall survival and progression-free survival...
August 10, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28795288/novel-agents-in-the-treatment-of-thymic-malignancies
#16
REVIEW
Claire Merveilleux du Vignaux, Jean-Michel Maury, Nicolas Girard
The management of thymic tumours is a paradigm of multidisciplinary collaboration. Chemotherapy may be administered part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy, or as an exclusive treatment if local treatment is not achievable. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. Given the limited activity of cytotoxic agents in the advanced, refractory setting, novel and innovative agents are needed...
August 10, 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28794469/targeting-the-pi3k-akt-mtor-signalling-pathway-in-cystic-fibrosis
#17
R Reilly, M S Mroz, E Dempsey, K Wynne, S J Keely, E F McKone, C Hiebel, C Behl, J A Coppinger
Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR) is a major cause of cystic fibrosis (CF), one of the most common inherited childhood diseases. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Using protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR...
August 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28791774/n-substituted-hydroxynapthalene-imino-oxindole-derivatives-as-new-class-of-pi3-kinase-inhibitor-and-breast-cancer-drug-molecular-validation-and-structure-activity-relationship-studies
#18
M Rajesh Kumar, Manikandan Alagumuthu, V Violet Dhayabaran
N-substituted hydroxynapthalene imino-oxindole derivatives (5a-g) were emerged as the inhibitors of the phosphoinositide 3-kinase (PI3K) which is a crucial regulator of apoptosis or programmed cell death. Electron donor/acceptor substituted indole-imine (5a-g) were achieved and the structures were elucidated by FTIR, 1H NMR, 13C NMR, and HRMS. PI3Ks inhibition potency was assessed by competitive ELISA. Subsequently, an anticancer activity against breast cancer (MCF-7) cell lines was evaluated. In both activities, compounds 5c, 5d, 5f and were showed most potent activities...
August 9, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28791407/long-non-coding-rna-meg3-inhibits-cell-growth-of-gliomas-by-targeting-mir-93-and-inactivating-pi3k-akt-pathway
#19
Ling Zhang, Xin Liang, Yuxiong Li
Gliomas are the most common cancers in the brain, accompanied with high morbility, occurrence, disability and mortality. Long non-coding RNAs (lncRNAs) have been proposed as promoter or inhibitor in many cancer processes. Previous findings have indicated that lncRNA-maternally expressed gene 3 (MEG3) is involved in tumorigenesis of several cancers, including glioma. However, the underlying mechanism of MEG3 in glioma remains elusive. In our study, MEG3 was found downregulated in glioma tissues compared with normal brain tissues...
August 3, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28791369/cepharanthine-hydrochloride-reverses-p%C3%A2-glycoprotein-mediated-multidrug-resistance-in-human-ovarian-carcinoma-a2780-taxol-cells-by-inhibiting-the-pi3k-akt-signaling-pathway
#20
Chen-Zheng Huang, Ya-Feng Wang, Yan Zhang, You-Mei Peng, Yi-Xian Liu, Fang Ma, Jin-Hua Jiang, Qing-Duan Wang
Ovarian cancer has the highest mortality rate among gynecologic malignant tumors. The major obstacle to treatment success is multidrug resistance (MDR) to chemotherapy drugs. Cepharanthine hydrochloride (CH), a natural alkaloid-derived compound, has shown MDR reversal potency in several tumor cell lines; however, the molecular mechanism is not entirely known. In the present study, we assessed whether CH sensitized malignant cells to chemotherapy drugs in ovarian cancer and explored the relevant mechanism. We found that CH reduced the IC50 value of paclitaxel and increased intracellular rhodamine-123 accumulation in human ovarian cancer A2780/Taxol cells in a concentration-dependent manner...
August 4, 2017: Oncology Reports
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