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https://www.readbyqxmd.com/read/29222171/tankyrase-inhibition-enhances-the-anti-proliferative-effect-of-pi3k-and-egfr-inhibition-mutually-affecting-%C3%AE-catenin-and-akt-signaling-in-colorectal-cancer
#1
Nina T Solberg, Jo Waaler, Kaja Lund, Line Mygland, Petter A Olsen, Stefan Krauss
Over-activation of the WNT/β-catenin signaling axis is a common denominator in colorectal cancer (CRC). Currently there is no available WNT inhibitor in clinical practice. Although tankyrase inhibitors have been proposed as promising candidates there are many CRC models that do not respond positively to tankyrase inhibition in vitro and in vivo. Therefore, a combinatorial therapeutic approach combining a tankyrase inhibitor (G007-LK) with PI3K (BKM120) and EGFR (Erlotinib) inhibitors in CRC was investigated...
December 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29198055/phase-ii-study-of-buparlisib-bkm120-and-trastuzumab-in-patients-with-her2-%C3%A2-locally-advanced-or-metastatic-breast-cancer-resistant-to-trastuzumab-based-therapy
#2
B Pistilli, T Pluard, A Urruticoechea, D Farci, A Kong, T Bachelot, S Chan, H S Han, G Jerusalem, P Urban, D Robinson, S L Mouhaër, E D Tomaso, C Massacesi, C Saura
PURPOSE: A Phase Ib study in patients with trastuzumab-resistant, human epidermal growth factor receptor-2- (HER2)-positive advanced breast cancer defined the recommended Phase II dose of buparlisib as 100 mg/day in combination with 2 mg/kg weekly trastuzumab, and reported preliminary signs of clinical activity. Here we present results from the Phase II portion. METHODS: Patients with trastuzumab-resistant, HER2-positive advanced breast cancer received buparlisib plus trastuzumab...
December 2, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29181846/golm1-promotes-prostate-cancer-progression-through-activating-pi3k-akt-mtor-signaling
#3
REVIEW
Guang Yan, Yi Ru, Kerong Wu, Fengqi Yan, Qinhao Wang, Jingxiang Wang, Tao Pan, Mei Zhang, Hua Han, Xia Li, Lian Zou
BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed cancer in men. Various molecular mechanisms account for PCa progression and elucidation of these mechanisms is key for selection of optimal therapies and improvement of patient outcome. Golgi membrane protein 1 (GOLM1) has been identified as a novel biomarker for PCa, but its biological functions and molecular mechanisms remain poorly understood. METHOD: GOLM1 expression was determined in PCa by tissue microarrays (TMAs) and real-time RT-PCR, Western blot, and immunohistochemistry (IHC) analyses...
November 27, 2017: Prostate
https://www.readbyqxmd.com/read/29151909/bkm120-sensitizes-c6-glioma-cells-to-temozolomide-via-suppression-of-the-pi3k-akt-nf-%C3%AE%C2%BAb-mgmt-signaling-pathway
#4
Mao Li, Ruo Fei Liang, Xiang Wang, Qing Mao, Yan Hui Liu
Glioblastoma is the most common type of malignant intracranial tumor in adults. Temozolomide (TMZ), as the first-line chemotherapy agent used in patients with glioblastoma, has demonstrated different effects in patients due to the expression of O6-methylguanine-DNA methyltransferase (MGMT) which is able to repair the DNA lesions induced by TMZ. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is over-activated in glioblastoma and has been revealed to be potentially implicated in resistance to TMZ...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29137323/nvp-bkm120-inhibits-colon-cancer-growth-via-foxo3a-dependent-puma-induction
#5
Shida Yang, Xin Li, Wenchang Guan, Mingqin Qian, Zhicheng Yao, Xiaoxue Yin, Hongmei Zhao
NVP-BKM120, a potent and highly selective PI3K inhibitor, is currently being investigated in phase I/II clinical trials. The mechanisms of action of NVP-BKM120 in colon cancer cells are unclear. In the present study, we investigated how NVP-BKM120 suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. We found that NVP-BKM120 treatment enhance PUMA induction irrespective of p53 status through the FoxO3a pathway following AKT inhibition. Furthermore, PUMA is required for NVP-BKM120-induced apoptosis in colon cancer cells...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29051320/combinatorial-treatment-with-mtor-inhibitors-and-streptozotocin-leads-to-synergistic-in-vitro-and-in-vivo-antitumor-effects-in-insulinoma-cells
#6
Julien Bollard, Céline Patte, Patrick Massoma, Isabelle Goddard, Nicolas Gadot, Noura Benslama, Valérie Hervieu, Carole Ferraro-Peyret, Martine Cordier-Bussat, Jean-Yves Scoazec, Colette Roche, Thomas Walter, Cécile Vercherat
Streptozotocin (STZ)-based chemotherapy is the first-line chemotherapy recommended for advanced pancreatic neuroendocrine tumors (pNETs), while targeted therapies, including mTOR inhibitors, are available in second-line treatment. Unfortunately objective response rates to both treatments are limited. Since mTOR pathway activation, commonly observed in pNETs, has been reported as one of the major mechanisms accounting for chemoresistance, we investigated the potential benefit of mTOR inhibition combined with STZ treatment in a subset of pNETs, namely insulinomas...
October 19, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29028222/role-of-rbp2-induced-er-and-igf1r-erbb-signaling-in-tamoxifen-resistance-in-breast-cancer
#7
Hee-Joo Choi, Hyeong-Seok Joo, Hee-Young Won, Kyueng-Whan Min, Hyung-Yong Kim, Taekwon Son, Young-Ha Oh, Jeong-Yeon Lee, Gu Kong
Background: Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Methods: Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764)...
April 1, 2018: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29024814/anti-tumor-effects-of-nvp-bkm120-alone-or-in-combination-with-mek162-in-biliary-tract-cancer
#8
Ling Jin, Mei-Hua Jin, Ah-Rong Nam, Ji-Eun Park, Ju-Hee Bang, Do-Youn Oh, Yung-Jue Bang
There are currently no clinically validated therapeutic targets for biliary tract cancer (BTC). Despite promising results in other cancers, compounds targeting the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, alone or in combination with Ras/Raf/MEK pathway inhibitors, have not been evaluated in BTC. Here, we examined the effects of a pan-PI3K inhibitor (BKM120) with or without a MEK inhibitor (MEK162), on eight human BTC cell lines carrying mutations in K-Ras and/or the PI3K catalytic subunit, PI3KCA...
October 9, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28989655/precision-spherical-nucleic-acids-for-delivery-of-anticancer-drugs
#9
Danny Bousmail, Lilian Amrein, Johans J Fakhoury, Hassan H Fakih, John C C Hsu, Lawrence Panasci, Hanadi F Sleiman
We report a spherical nucleic acid (SNA) system for the delivery of BKM120, an anticancer drug for treatment of chronic lymphocytic leukemia (CLL). While promising for cancer treatment, this drug crosses the blood-brain barrier causing significant side-effects in patients. The DNA nanoparticle encapsulates BKM120 in high efficiency, and is unparalleled in its monodispersity, ease of synthesis and stability in different biological media and in serum. These DNA nanostructures demonstrate efficient uptake in human cervical cancer (HeLa) cells, and increased internalization of cargo...
September 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28971900/pan-phosphatidylinositol-3-kinase-inhibition-with-buparlisib-in-patients-with-relapsed-and-refractory-non-hodgkin-lymphoma
#10
Anas Younes, Gilles Salles, Giovanni Martinelli, Robert Gregory Bociek, Dolores Caballero Barrigon, Eva González Barca, Mehmet Turgut, John Gerecitano, Oliver Kong, Chaitali Babanrao Pisal, Ranjana Tavorath, Won Seog Kim
Phosphatidylinositol 3-kinase mechanistic target of rapamycin pathway activation plays a role in the pathogenesis of non-Hodgkin lymphoma. This multicenter, open-label Phase II study evaluated buparlisib (BKM120), a pan-class I Phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or refractory non-Hodgkin lymphoma. Patients received buparlisib 100 mg once daily in three separate cohorts (diffuse large B-cell lymphoma, mantle cell lymphoma, or follicular lymphoma) until progression, intolerance, or withdrawal of consent...
September 29, 2017: Haematologica
https://www.readbyqxmd.com/read/28945228/erk-dependent-il-6-autocrine-signaling-mediates-adaptive-resistance-to-pan-pi3k-inhibitor-bkm120-in-head-and-neck-squamous-cell-carcinoma
#11
M R Yun, H M Choi, H N Kang, Yw Lee, H-S Joo, D H Kim, H R Kim, M H Hong, S O Yoon, B C Cho
Hyperactivation of phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in head and neck squamous cell carcinoma (HNSCC). However, clinical outcomes of targeting the PI3K pathway have been underwhelming. In present study, we investigated the resistant mechanisms and potential combination therapeutic strategy to overcome adaptive resistance to PI3K inhibitor in HNSCC. Treatment of NVP-BKM120, a pan-PI3K inhibitor, led to upregulation of interleukin-6 (IL-6) and subsequent activation of either extracellular signal-regulated kinase (ERK) or signal transducers and activators of transcription 3 (STAT3), causing modest antitumor effects on the growth of HNSCC cells...
September 25, 2017: Oncogene
https://www.readbyqxmd.com/read/28945226/pten-deficiency-sensitizes-endometrioid-endometrial-cancer-to-compound-parp-pi3k-inhibition-but-not-parp-inhibition-as-monotherapy
#12
X Bian, J Gao, F Luo, C Rui, T Zheng, D Wang, Y Wang, T M Roberts, P Liu, J J Zhao, H Cheng
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising cancer therapeutics especially for tumors with deficient homologous recombination (HR) repair. However, as HR-deficient tumors represent only a small fraction of endometrial cancers, the therapeutic utility of PARP inhibitors is limited in this disease. Somatic loss of phosphatase and tensin homolog (PTEN), a tumor suppressor that counteracts phosphoinositide 3-kinase (PI3K) activity, is one of the most common genetic aberrations in endometrioid endometrial cancer...
September 25, 2017: Oncogene
https://www.readbyqxmd.com/read/28835385/targeting-phosphatidylinositol-3-kinase-signaling-pathway-for-therapeutic-enhancement-of-vascular-targeted-photodynamic-therapy
#13
Daniel Kraus, Pratheeba Palasuberniam, Bin Chen
Vascular-targeted photodynamic therapy (PDT) selectively disrupts vascular function by inducing oxidative damages to the vasculature, particularly endothelial cells. Although effective tumor eradication and excellent safety profile are well demonstrated in both preclinical and clinical studies, incomplete vascular shutdown and angiogenesis are known to cause tumor recurrence after vascular-targeted PDT. We have explored therapeutic enhancement of vascular-targeted PDT with PI3K signaling pathway inhibitors because the activation of PI3K pathway was involved in promoting endothelial cell survival and proliferation after PDT...
November 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28834761/novel-pan-pi3k-inhibitor-induced-apoptosis-in-apl-cells-correlates-with-suppression-of-telomerase-an-emerging-mechanism-of-action-of-bkm120
#14
Davood Bashash, Mahda Delshad, Ava Safaroghli-Azar, Majid Safa, Majid Momeny, Seyed H Ghaffari
The intertwining between cancer pathogenesis and perturbation of multitude signaling pathways ushered the cancer therapeutic approaches into an unbounded route of targeted therapies. For the nonce and among the plethora of promising inhibitors, intense interest has focused on small molecules targeting different component of PI3K axis. Intrigued by the constant activation of PI3K in leukemia, this study aimed to investigate the effects of BKM120, as the excelled member of pan PI3K inhibitors, in a panel of hematologic malignant cell lines...
October 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28829592/5-4-6-dimorpholino-1-3-5-triazin-2-yl-4-trifluoromethyl-pyridin-2-amine-pqr309-a-potent-brain-penetrant-orally-bioavailable-pan-class-i-pi3k-mtor-inhibitor-as-clinical-candidate-in-oncology
#15
Florent Beaufils, Natasa Cmiljanovic, Vladimir Cmiljanovic, Thomas Bohnacker, Anna Melone, Romina Marone, Eileen Jackson, Xuxiao Zhang, Alexander Sele, Chiara Borsari, Jürgen Mestan, Paul Hebeisen, Petra Hillmann, Bernd Giese, Marketa Zvelebil, Doriano Fabbro, Roger L Williams, Denise Rageot, Matthias P Wymann
Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays...
September 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28662162/bkm120-induces-apoptosis-and-inhibits-tumor-growth-in-medulloblastoma
#16
Ping Zhao, Jacob Hall, Mary Durston, Austin Voydanoff, Elizabeth VanSickle, Shannon Kelly, Abhinav B Nagulapally, Jeffery Bond, Giselle Saulnier Sholler
Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for nearly 20 percent of all childhood brain tumors. New treatment strategies are needed to improve patient survival outcomes and to reduce adverse effects of current therapy. The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) intracellular signaling pathway plays a key role in cellular metabolism, proliferation, survival and angiogenesis, and is often constitutively activated in human cancers, providing unique opportunities for anticancer therapeutic intervention...
2017: PloS One
https://www.readbyqxmd.com/read/28606464/corrigendum-to-phase-ib-dose-finding-study-of-abiraterone-acetate-plus-buparlisib-bkm120-or-dactolisib-bez235-in-patients-with-castration-resistant-prostate-cancer-european-journal-of-cancer-76-2017-36-44
#17
Christophe Massard, Kim Nguyen Chi, Daniel Castellano, Johann de Bono, Gwenaelle Gravis, Luc Dirix, Jean-Pascal Machiels, Alain Mita, Begoña Mellado, Sabine Turri, Joan Maier, Denes Csonka, Arunava Chakravartty, Karim Fizazi
No abstract text is available yet for this article.
August 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28586756/inhibitors-of-the-pi3k-mtor-pathway-prevent-stat5-phosphorylation-in-jak2v617f-mutated-cells-through-pp2a-cip2a-axis
#18
Niccolò Bartalucci, Laura Calabresi, Manjola Balliu, Serena Martinelli, Maria Caterina Rossi, Jean Luc Villeval, Francesco Annunziato, Paola Guglielmelli, Alessandro M Vannucchi
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...
May 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28486691/combined-kinase-inhibitors-of-mek1-2-and-either-pi3k-or-pdgfr-are-efficacious-in-intracranial-triple-negative-breast-cancer
#19
Amanda E D Van Swearingen, Maria J Sambade, Marni B Siegel, Shivani Sud, Robert S McNeill, Samantha M Bevill, Xin Chen, Ryan E Bash, Louisa Mounsey, Brian T Golitz, Charlene Santos, Allison Deal, Joel S Parker, Naim Rashid, C Ryan Miller, Gary L Johnson, Carey K Anders
Background: Triple-negative breast cancer (TNBC), lacking expression of hormone and human epidermal growth factor receptor 2 receptors, is an aggressive subtype that frequently metastasizes to the brain and has no FDA-approved systemic therapies. Previous literature demonstrates mitogen-activated protein kinase kinase (MEK) pathway activation in TNBC brain metastases. Thus, we aimed to discover rational combinatorial therapies with MEK inhibition, hypothesizing that co-inhibition using clinically available brain-penetrant inhibitors would improve survival in preclinical models of TNBC brain metastases...
October 19, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28484083/pi3k-inhibitor-enhances-the-cytotoxic-response-to-etoposide-and-cisplatin-in-a-newly-established-neuroendocrine-cervical-carcinoma-cell-line
#20
Zih-Yin Lai, Hsin-Yueh Yeo, Ya-Tse Chen, Kuo-Ming Chang, Tze-Chien Chen, Yung-Jen Chuang, Shing-Jyh Chang
BACKGROUND: Neuroendocrine cervical carcinoma (NECC) is a rare and aggressive subtype of cervical cancer. To date, no NECC cell-based model is available, which hinders the development of new therapeutic strategies for NECC. In this study, we derived a new NECC cell line from an ex vivo biopsy and used it to explore novel drug combination approach for NECC. RESULTS: The stable HM-1 cell line displayed high expression levels of the neuroendocrine marker, synaptophysin...
July 11, 2017: Oncotarget
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