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https://www.readbyqxmd.com/read/28072765/phase-ii-study-of-the-pi3k-inhibitor-bkm120-in-patients-with-advanced-or-recurrent-endometrial-carcinoma-a-stratified-type-i-type-ii-study-from-the-gineco-group
#1
P-E Heudel, M Fabbro, C Roemer-Becuwe, M C Kaminsky, A Arnaud, F Joly, S Roche-Forestier, J Meunier, C Foa, B You, F Priou, Y Tazi, A Floquet, F Selle, D Berton-Rigaud, A Lesoin, E Kalbacher, A Lortholary, L Favier, I Treilleux, I Ray-Coquard
: Backround:Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma. METHODS: This phase II, multicentre, single-arm, double strata (histological low grade (LG) or high grade (HG)) open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma who had received not more than one prior chemotherapy regimen...
January 10, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28036259/subcellular-localization-of-foxo3a-as-a-potential-biomarker-of-response-to-combined-treatment-with-inhibitors-of-pi3k-and-autophagy-in-pik3ca-mutant-cancer-cells
#2
Hyun-Jung Kim, Soo Yoon Lee, Chan Young Kim, Yun Hwan Kim, Woong Ju, Seung Chloe Kim
Autophagy is the process of lysosome-mediated degradation and recycling that functions as an adaptive survival mechanism during anti-cancer therapy. Aberrant activation of the phosphoinositide-3-kinase (PI3K) pathway frequently occurs in solid tumors, including cervical cancer. However, single-agent PI3K inhibitors show modest anti-tumor efficacy in clinics. To see whether autophagy inhibition improves the efficacy of PI3K inhibitor in PIK3CA-mutant cancer cells, cells were treated with BKM120, a pan-PI3K inhibitor, and the autophagy inhibitor hydroxychloroquine (HCQ)...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/28004037/differential-compensation-mechanisms-define-resistance-to-pi3k-inhibitors-in-pik3ca-amplified-hnscc
#3
Nicole L Michmerhuizen, Elizabeth Leonard, Aditi Kulkarni, J Chad Brenner
OBJECTIVE: Recent sequencing studies of head and neck squamous cell carcinomas (HNSCCs) have identified the phosphatidylinositol 3-kinase (PI3K) pathway as the most frequently mutated, oncogenic pathway in this cancer type. Despite the frequency of activating genomic alterations in PIK3CA (the gene encoding the catalytic subunit of PI3K, targeted inhibitors of PI3K have not shown clinical efficacy as monotherapies. We hypothesized that co-dependent pathways, including the Ras-MEK-ERK pathway, may still be functional in the presence of PI3K inhibitors and might serve as mediators of this resistance...
2016: Otorhinolaryngol Head Neck Surg
https://www.readbyqxmd.com/read/28003307/pi3k-inhibition-reduces-mammary-tumor-growth-and-facilitates-anti-tumor-immunity-and-anti-pd1-responses
#4
Jiqing Sai, Philip Owens, Sergey V Novitiskiy, Oriana E Hawkins, Anna E Vilgelm, Jinming Yang, Tammy Sobolik-Delmaire, Nicole Lavender, Andrew C Johnson, Colt McClain, Gregory D Ayers, Mark C Kelley, Melinda Sanders, Ingrid A Mayer, Harold L Moses, Mark Boothby, Ann Richmond
PURPOSE: Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3Kα,β in tumor growth and PI3Kγ,δ in immune cell function, we sought to determine whether PI3K inhibition altered anti-tumor immunity. EXPERIMENTAL DESIGN: The effect of PI3K inhibition on tumor growth, metastasis, and anti-tumor immune response was characterized in mouse models utilizing orthotopic implants of 4T1 or PyMT mammary tumors into syngeneic or PI3Kγ null mice, and patient-derived breast cancer xenografts in humanized mice...
December 21, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28002802/dual-inhibition-of-the-pi3k-akt-mtor-pathway-suppresses-the-growth-of-leiomyosarcomas-but-leads-to-erk-activation-through-mtorc2-biological-and-clinical-implications
#5
Benjamin Fourneaux, Vanessa Chaire, Carlo Lucchesi, Marie Karanian, Raphael Pineau, Audrey Laroche-Clary, Antoine Italiano
The PI3K/AKT/mTOR pathway plays a crucial role in the development of leiomyosarcomas (LMSs). In this study, we tested the efficacy of dual PI3K/mTOR (BEZ235), PI3K (BKM120) and mTOR (everolimus) inhibitors in three human LMS cell lines. In vitro and in vivo studies using LMS cell lines showed that BEZ235 has a significantly higher anti-tumor effect than either BKM120 or everolimus, resulting in a greater reduction in tumor growth and more pronounced inhibitory effects on mitotic activity and PI3K/AKT/mTOR signaling...
December 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27993796/phase-i-dose-escalation-study-of-the-pi3kinase-pathway-inhibitor-bkm120-and-the-oral-poly-adp-ribose-polymerase-parp-inhibitor-olaparib-for-the-treatment-of-high-grade-serous-ovarian-and-breast-cancer
#6
U A Matulonis, G M Wulf, W T Barry, M Birrer, S N Westin, S Farooq, K M Bell-McGuinn, E Obermayer, C Whalen, T Spagnoletti, W Luo, H Liu, R C Hok, C Aghajanian, D B Solit, G B Mills, B S Taylor, H Won, M F Berger, S Palakurthi, J Liu, L C Cantley, E Winer
BACKGROUND: Based upon preclinical synergy in murine models, we performed a phase 1 trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. PATIENTS AND METHODS: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles...
December 19, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27803006/a-randomized-adaptive-phase-ii-iii-study-of-buparlisib-a-pan-class-i-pi3k-inhibitor-combined-with-paclitaxel-for-the-treatment-of-her2-advanced-breast-cancer-belle-4
#7
M Martín, A Chan, L Dirix, J O'Shaughnessy, R Hegg, A Manikhas, M Shtivelband, P Krivorotko, N Batista López, M Campone, M Ruiz Borrego, Q J Khan, J T Beck, M Ramos Vázquez, P Urban, S Goteti, E Di Tomaso, C Massacesi, S Delaloge
BACKGROUND: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. PATIENTS AND METHODS: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease...
November 1, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27793950/phase-i-study-of-the-pan-pi3k-inhibitor-buparlisib-in-adult-chinese-patients-with-advanced-solid-tumors
#8
Yi-Long Wu, L I Zhang, Lucia Trandafir, Tuochuan Dong, Vincent Duval, Katharine Hazell, Binghe Xu
BACKGROUND/AIM: The phosphatidylinositol-3-kinase (PI3K) signaling pathway is frequently activated in cancer. Buparlisib (BKM120), an oral pan-PI3K inhibitor, inhibits proliferation of human cancer in preclinical models. Studies of buparlisib in Western and Japanese adults with advanced solid tumors established a recommended dose of 100 mg/day and showed an acceptable safety profile and evidence of efficacy. This phase I dose-escalation/expansion study aimed to establish the maximum tolerated dose (MTD) of single-agent, once daily oral buparlisib in Chinese patients with advanced solid tumors...
2016: Anticancer Research
https://www.readbyqxmd.com/read/27783994/combination-effect-of-therapies-targeting-the-pi3k-and-ar-signaling-pathways-in-prostate-cancer
#9
Shalini Singh Yadav, Jinyi Li, Jennifer A Stockert, James O'Connor, Bryan Herzog, Cordelia Elaiho, Matthew D Galsky, Ashutosh Kumar Tewari, Kamlesh Kumar Yadav
Several promising targeted-therapeutics for prostate cancer (PCa), primarily affecting the androgen receptor (AR) and the PI3K/AKT/mTOR-pathway, are in various phases of development. However, despite promise, single-agent inhibitors targeting the two pathways have not shown long-term benefits, perhaps due to a complex compensatory cross talk that exists between the two pathways. Combination therapy has thus been proposed to maximize benefit. We have carried out a systematic study of two-drug combination effect of MDV3100 (AR antagonist), BKM120 (PI3K inhibitor), TKI258 (pan RTK inhibitor) and RAD001 (mTOR inhibitor) using various PCa cell lines...
October 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27765055/targeting-of-pi3k-akt-mtor-pathway-to-inhibit-t-cell-activation-and-prevent-graft-versus-host-disease-development
#10
Mª Carmen Herrero-Sánchez, Concepción Rodríguez-Serrano, Julia Almeida, Laura San Segundo, Susana Inogés, Ángel Santos-Briz, Jesús García-Briñón, Luis Antonio Corchete, Jesús F San Miguel, Consuelo Del Cañizo, Belén Blanco
BACKGROUND: Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect...
October 20, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27673440/buparlisib-a-pi3k-inhibitor-demonstrates-acceptable-tolerability-and-preliminary-activity-in-a-phase-i-trial-of-patients-with-advanced-leukemias
#11
Brittany Knick Ragon, Hagop Kantarjian, Elias Jabbour, Farhad Ravandi, Jorge Cortes, Gautam Borthakur, LaKiesha DeBose, Zhihong Zeng, Heather Schneider, Naveen Pemmaraju, Guillermo Garcia-Manero, Steven Kornblau, William Wierda, Jan Burger, Courtney D DiNardo, Michael Andreeff, Marina Konopleva, Naval Daver
Phosphatidylinositol-3-kinase (PI3K) signaling plays a crucial role in oncogene-mediated tumor growth and proliferation. Buparlisib (BKM120) is an oral pan-class I PI3K inhibitor. This phase I study was conducted to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of BKM120 in patients (pts) with relapsed/refractory acute leukemias. Fourteen pts (12 acute myeloid leukemia, 1 acute lymphoblastic leukemia, and 1 mixed phenotype leukemia) were enrolled. Twelve pts received BKM-120 80 mg/day and two 100 mg/day...
January 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/27639383/addition-of-the-p110%C3%AE-inhibitor-byl719-overcomes-targeted-therapy-resistance-in-cells-from-her2-positive-pten-loss-breast-cancer
#12
Chen Zhang, Bingfei Xu, Pian Liu
Breast cancer is one of the leading causes of death for women worldwide. Among various subtypes of breast cancer, human epidermal growth factor receptor 2 (HER2)-positive and phosphatase and tensin homolog (PTEN) loss breast cancer is a cause of great concern in terms of its resistance to HER2-targeted therapies and its poor prognosis. Phosphatidylinositol 3-kinase (PI3K)/AKT hyperphosphorylation is considered one of key mechanisms leading to this resistance, thus combination therapy of PI3K inhibitors and HER2 antibodies is promising for overcoming this problem, and more specific regimens should be designed in this age of precision medicine...
November 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/27623107/pi3-kinase-pathway-and-met-inhibition-is-efficacious-in-malignant-pleural-mesothelioma
#13
Rajani Kanteti, Jacob J Riehm, Immanuel Dhanasingh, Frances E Lennon, Tamara Mirzapoiazova, Bolot Mambetsariev, Hedy L Kindler, Ravi Salgia
Malignant pleural mesothelioma (MPM) is an aggressive cancer that is commonly associated with prior asbestos exposure. Receptor tyrosine kinases (RTKs) such as MET and its downstream target PI3K are overexpressed and activated in a majority of MPMs. Here, we studied the combinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K inhibitor, BKM120, or with a PI3K/mTOR dual inhibitor, GDC-0980, in mesothelioma. Cell viability results showed that MPM cells were highly sensitive to crizotinib, BKM120 and GDC-0980 when used individually and their combination was more effective in suppressing growth...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27599915/inhibitor-of-pan-class-i-pi3k-induces-differentially-apoptotic-pathways-in-acute-leukemia-cells-shedding-new-light-on-nvp-bkm120-mechanism-of-action
#14
Davood Bashash, Ava Safaroghli-Azar, Mahda Delshad, Samaneh Bayati, Elaheh Nooshinfar, Seyed H Ghaffari
Complex interplay of intracellular signaling networks, spanning from the extracellular environment to the nucleus, orchestrate normal cell growth and survival. Dysregulation of such signals contributes to malignant transformation, thereby giving the cancer cells a survival advantage, but also could be exploited for new anticancer interventions. The aim of this study was to investigate the effects of pan class-I PI3K inhibitor NVP-BKM120 on two distinct acute leukemia cell lines, NB4 (with mutant p53) and Nalm-6 (with wild-type p53)...
October 2016: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/27572309/blockade-efficacy-of-mek-erk-dependent-autophagy-enhances-pi3k-akt-inhibitor-nvp-bkm120-s-therapeutic-effectiveness-in-lung-cancer-cells
#15
Hui Ren, Hua Guo, Asmitananda Thakur, Shuo Zhang, Ting Wang, Yiqian Liang, Puyu Shi, Lei Gao, Feng Liu, Jing Feng, Tianjun Chen, Tian Yang, Dong Shang, Johnson J Liu, Feng Xu, Mingwei Chen
NVP-BKM120 (BKM120) is a new pan-class I phosphatidylinositol-3 kinase (PI3K) inhibitor and has been tested in clinical trials as an anticancer agent. In this study, we determined whether BKM120 induces autophagy and the impact of autophagy induction on BKM120's growth-inhibitory activity. BKM120 potently induced elevation of autophagosome-bound type II LC3 (LC3-II) protein, predominantly in cell lines insensitive to BKM120, thereby inducing autophagy. The presence of lysosomal protease inhibitor chloroquine further enhanced the levels of LC3-II...
October 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27568979/silencing-vimentin-expression-decreases-pulmonary-metastases-in-a-pre-diabetic-mouse-model-of-mammary-tumor-progression
#16
Z Zelenko, E J Gallagher, A Tobin-Hess, V Belardi, R Rostoker, J Blank, Y Dina, D LeRoith
Increased breast cancer risk and mortality has been associated with obesity and type 2 diabetes (T2D). Hyperinsulinemia, a key factor in obesity, pre-diabetes and T2D, has been associated with decreased breast cancer survival. In this study, a mouse model of pre-diabetes (MKR mouse) was used to investigate the mechanisms through which endogenous hyperinsulinemia promotes mammary tumor metastases. The MKR mice developed larger primary tumors and greater number of pulmonary metastases compared with wild-type (WT) mice after injection with c-Myc/Vegf overexpressing MVT-1 cells...
August 29, 2016: Oncogene
https://www.readbyqxmd.com/read/27531477/-molecular-mechanisms-of-resistance-to-phosphatidyl-inositol-3-kinase-inhibitors-in-triple-negative-breast-cancer-cells
#17
W L Zhang, W J Ma, S Chen, X Z Wu, H R Zhang, J H Zhang
OBJECTIVE: To explore the molecular mechanisms of resistance to phosphatidyl inositol 3-kinase (PI3K) inhibitors in triple-negative breast cancer (TNBC) cells. METHODS: HCC70 cells (TNBC) were transfected with siFZD7, siWANT5B or siGSK3 using lipofectamine 2000 transfection reagent. The expression levels of key proteins of WNT/β-catenin and PI3K/AKT/mTOR pathways were determined by Western blot analysis. After HCC70, MCF-7 (ER-positive) and SK-BR3 (HER2-positive) cells were treated with PI3K/AKT/mTOR inhibitors, the inhibition rates of cell proliferation were measured by MTT assay, and half maximal inhibitory concentrations (IC50) were calculated...
August 2016: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
https://www.readbyqxmd.com/read/27507562/combination-of-phosphotidylinositol-3-kinase-targeting-with-cetuximab-and-irradiation-a-preclinical-study-on-an-orthotopic-xenograft-model-of-head-and-neck-cancer
#18
Alexandre Bozec, Nathalie Ebran, Nina Radosevic-Robin, Emmanuel Chamorey, Hedi Ben Yahia, Serge Marcie, Mathieu Gautier, Frédérique Penault-Llorca, Gérard Milano
BACKGROUND: The purpose of this study was to investigate the effects of combining the phosphotidylinositol-3-kinase (PI3K) inhibitor buparlisib (BKM)120 with the anti-epidermal growth factor receptor (EGFR) agent cetuximab and radiotherapy (RT) on an orthotopic model of head and neck squamous cell carcinoma (HNSCC). METHODS: We evaluated the antitumor efficacy of BKM120, cetuximab, and RT, administered alone or in combination, using the human PIK3CA-mutated HNSCC cell line, CAL33, injected into the floor of the mouth of nude mice...
January 2017: Head & Neck
https://www.readbyqxmd.com/read/27439454/novel-phosphatidylinositol-3-kinase-inhibitor-bkm120-enhances-the-sensitivity-of-multiple-myeloma-to-bortezomib-and-overcomes-resistance
#19
Wenjun Yu, Yubao Chen, Rufang Xiang, Wenbin Xu, Yan Wang, Jia Tong, Nan Zhang, Yingli Wu, Hua Yan
Proteasome inhibitor bortezomib has proven efficacy against multiple myeloma. However, bortezomib activates the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway (which is essential to the development of myeloma), often resulting in drug resistance and disease recurrence. The addition of BKM120 significantly enhanced the apoptotic effects of bortezomib in both bortezomib-sensitive and bortezomib-resistant cells. Treatment with bortezomib alone increased the phosphorylation of AKT (P-AKT), whereas the addition of BKM120 markedly downregulated P-AKT in both bortezomib-sensitive and bortezomib-resistant cells...
July 20, 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27426307/combined-inhibition-of-pi3k-and-parp-is-effective-in-the-treatment-of-ovarian-cancer-cells-with-wild-type-pik3ca-genes
#20
Dong Wang, Chengbo Li, Yuan Zhang, Min Wang, Nan Jiang, Lin Xiang, Ting Li, Thomas M Roberts, Jean J Zhao, Hailing Cheng, Pixu Liu
OBJECTIVE: Combined inhibition of PI3K and PARP has been shown to be effective in the treatment of preclinical models of breast cancer and prostate cancer independent of BRCA or PIK3CA mutational status. However, the knowledge about this combination treatment in ovarian cancer is limited. The aim of this study was to evaluate the therapeutic effect of PI3K inhibitor BKM120 and PARP inhibitor Olaparib on ovarian cancer cell lines bearing wild-type PIK3CA genes. METHODS: We exposed three wild-type PIK3CA ovarian cancer cell lines to a PI3K inhibitor BKM120 and/or a PARP inhibitor Olaparib...
September 2016: Gynecologic Oncology
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