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https://www.readbyqxmd.com/read/27831000/targeted-therapies-for-the-treatment-of-non-small-cell-lung-cancer-monoclonal-antibodies-and-biological-inhibitors
#1
Ana P S Silva, Priscila V Coelho, Maristella Anazetti, Patricia U Simioni
The usual treatments for patients with non-small-cell lung cancer (NSCLC), such as advanced lung adenocarcinoma, are unspecific and aggressive, and include lung resection, radiotherapy and chemotherapy. Recently, treatment with monoclonal antibodies and biological inhibitors has emerged as an effective alternative, generating effective results with few side effects. In recent years, several clinical trials using monoclonal antibodies presented potential benefits to NSCLC, and four of them are already approved for the treatment of NSCLC, such as cetuximab, bevacizumab, nivolumab and pembrolizumab...
November 10, 2016: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/27811010/dual-inhibition-of-mek-and-pi3k-akt-rescues-cancer-cachexia-through-both-tumor-extrinsic-and-intrinsic-activities
#2
Erin E Talbert, Jennifer Yang, Thomas A Mace, Matthew R Farren, Alton B Farris, Gregory S Young, Omar Elnaggar, Zheng Che, Cynthia D Timmers, Priyani Rajasekera, Jennifer M Maskarinec, Mark Bloomston, Tanios Bekaii-Saab, Denis C Guttridge, Gregory B Lesinski
Involuntary weight loss, a part of the cachexia syndrome, is a debilitating co-morbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses, but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEK inhibition might be anti-cachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK½ inhibitor MEK162...
November 3, 2016: Molecular Cancer Therapeutics
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
#3
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
#4
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...
November 2016: Anticancer Research
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
#5
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, 1 mixed phenotype leukemia) were enrolled. Twelve pts received BKM-120 80 mg/day and two 100 mg/day...
September 27, 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/27579615/janus-and-pi3-kinases-mediate-glucocorticoid-resistance-in-activated-chronic-leukemia-cells
#6
Sina Oppermann, Avery J Lam, Stephanie Tung, Yonghong Shi, Lindsay McCaw, Guizhei Wang, Jarkko Ylanko, Brian Leber, David Andrews, David E Spaner
Glucorticoids (GCs) such as dexamethasone (DEX) remain important treatments for Chronic Lymphocytic Leukemia (CLL) but the mechanisms are poorly understood and resistance is inevitable. Proliferation centers (PC) in lymph nodes and bone marrow offer protection against many cytotoxic drugs and circulating CLL cells were found to acquire resistance to DEX-mediated killing in conditions encountered in PCs including stimulation by toll-like receptor agonists and interactions with stromal cells. The resistant state was associated with impaired glucocorticoid receptor-mediated gene expression, autocrine activation of STAT3 through Janus Kinases (JAKs), and increased glycolysis...
August 25, 2016: Oncotarget
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
#7
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...
August 10, 2016: Head & Neck
https://www.readbyqxmd.com/read/27307593/pi3k-pathway-inhibition-achieves-potent-antitumor-activity-in-melanoma-brain-metastases-in-vitro-and-in-vivo
#8
Heike Niessner, Jennifer Schmitz, Ghazaleh Tabatabai, Andreas M Schmid, Carsten Calaminus, Tobias Sinnberg, Benjamin Weide, Thomas K Eigentler, Claus Garbe, Birgit Schittek, Leticia Quintanilla-Fend, Benjamin Bender, Marion Mai, Christian Praetorius, Stefan Beissert, Gabriele Schackert, Michael H Muders, Matthias Meinhardt, Gustavo B Baretton, Reinhard Dummer, Keith Flaherty, Bernd J Pichler, Dagmar Kulms, Dana Westphal, Friedegund Meier
PURPOSE: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for "brain-specific" therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases...
December 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27283525/treatment-with-the-pi3k-inhibitor-buparlisib-nvp-bkm120-suppresses-the-growth-of-established-patient-derived-gbm-xenografts-and-prolongs-survival-in-nude-rats
#9
I A Netland, H E Førde, L Sleire, L Leiss, M A Rahman, B S Skeie, H Miletic, P Ø Enger, D Goplen
Glioblastomas (GBMs) are aggressive brain tumours with a dismal prognosis, despite combined surgery, radio- and chemotherapy. Close to 90 % of all GBMs harbour a deregulated PI3K pathway, which is essential in regulating central cellular functions such as proliferation, cell growth, motility and survival. Thus, PI3K represents a potential target for molecular therapy in GBM. We investigated the anti-tumour efficacy of the PI3K inhibitor buparlisib (NVP-BKM120) in GBM cell lines in vitro and in vivo, when treatment was initiated after MRI-confirmed tumour engraftment...
August 2016: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/27259258/multi-kinase-inhibitors-interact-with-sildenafil-and-erbb1-2-4-inhibitors-to-kill-tumor-cells-in-vitro-and-in-vivo
#10
Laurence Booth, Thomas Albers, Jane L Roberts, Mehrad Tavallai, Andrew Poklepovic, Iryna O Lebedyeva, Paul Dent
We have recently demonstrated that multi-kinase inhibitors such as sorafenib and pazopanib can suppress the detection of chaperones by in situ immuno-fluorescence, which is further enhanced by phosphodiesterase 5 inhibitors. Sorafenib and pazopanib inhibited the HSP90 ATPase activity with IC50 values of ~1.0 μM and ~75 nM, respectively. Pazopanib docked in silico with two possible poses into the HSP90 ATP binding pocket. Pazopanib and sildenafil combined to reduce the total protein levels of HSP1H/p105 and c-MYC and to reduce their co-localization...
May 31, 2016: Oncotarget
https://www.readbyqxmd.com/read/27220784/-combination-therapy-of-molecular-targeted-drugs-for-breast-cancer-their-potential-in-the-future
#11
Maiko Okano, Tohru Ohtake, Shigehira Saji
In breast cancer treatment, molecular-targeted drugs such as trastuzumab and lapatinib have been used for many y ears, and the benefits have been seen in many patients. The molecular-targeted drugs have mainly been used in combination with cytotoxic agents; however, combination therapies with 2 molecular-targeted drugs are currently being investigated. The combination therapy of 2 HER2 receptor antibodies, pertuzumab and trastuzumab, has tremendous benefit for HER2 positive metastatic breast cancer patients...
April 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/27198170/a-phase-1-study-of-buparlisib-and-bevacizumab-in-patients-with-metastatic-renal-cell-carcinoma-progressing-on-vascular-endothelial-growth-factor-targeted-therapies
#12
Rana R McKay, Guillermo De Velasco, Lillian Werner, Joaquim Bellmunt, Lauren Harshman, Christopher Sweeney, Jonathan E Rosenberg, Michelle Hirsch, Sabina Signoretti, Eliezer M Van Allen, Meghara Walsh, Ulka Vaishampayan, David F McDermott, Toni K Choueiri
BACKGROUND: The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is dysregulated in patients with metastatic renal cell carcinoma (mRCC). Buparlisib is a pan-PI3K inhibitor with activity in advanced solid tumors. The primary objective of the current study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of buparlisib and bevacizumab in patients with mRCC. Secondary objectives included efficacy, biomarker discovery, and additional toxicity...
August 1, 2016: Cancer
https://www.readbyqxmd.com/read/26983879/differential-effects-of-pi3k-and-dual-pi3k-mtor-inhibition-in-rat-prolactin-secreting-pituitary-tumors
#13
Marie Chanal, Pascale Chevallier, Véronique Raverot, Guillaume Fonteneau, Kristin Lucia, Jose Luis Monteserin Garcia, Alexa Rachwan, Emmanuel Jouanneau, Jacqueline Trouillas, Jérôme Honnorat, Carole Auger, Marily Theodoropoulou, Gérald Raverot
Aggressive pituitary tumors are rare but difficult to manage, as there is no effective chemotherapy to restrict their growth and cause their shrinkage. Within these tumors, growth-promoting cascades, like the PI3K/mTOR pathway, appear to be activated. We tested the efficacy of two inhibitors of this pathway, NVP-BKM120 (Buparlisib; pan-PI3K) and NVP-BEZ235 (dual PI3K/mTOR), both in vitro on immortalized pituitary tumor cells (GH3) and on primary cell cultures of human pituitary tumors and in vivo on a rat model of prolactin (PRL) tumors (SMtTW3)...
June 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/26846842/bkm-120-buparlisib-a-phosphatidyl-inositol-3-kinase-inhibitor-with-anti-invasive-properties-in-glioblastoma
#14
Maria-Carmela Speranza, Michal O Nowicki, Prajna Behera, Choi-Fong Cho, E Antonio Chiocca, Sean E Lawler
Glioblastoma is an aggressive, invasive tumor of the central nervous system (CNS). There is a widely acknowledged need for anti-invasive therapeutics to limit glioblastoma invasion. BKM-120 is a CNS-penetrant pan-class I phosphatidyl-inositol-3 kinase (PI3K) inhibitor in clinical trials for solid tumors, including glioblastoma. We observed that BKM-120 has potent anti-invasive effects in glioblastoma cell lines and patient-derived glioma cells in vitro. These anti-migratory effects were clearly distinguishable from cytostatic and cytotoxic effects at higher drug concentrations and longer durations of drug exposure...
2016: Scientific Reports
https://www.readbyqxmd.com/read/26830312/treatment-strategies-for-advanced-hormone-receptor-positive-and-human-epidermal-growth-factor-2-negative-breast-cancer-the-role-of-treatment-order
#15
Edith A Perez
Although survival rates among patients with breast cancer have improved in recent years, those diagnosed with advanced disease with distant metastasis face a 5-year survival rate of less than 25%, making the management of these patients an area still in significant need of continued research. Selecting the optimal treatment order from among the variety of currently available therapy options presents a relevant challenge for medical oncologists. With the understanding that the majority of patients with breast cancer and those who succumb to this disease have HR-positive disease, this review will focus on treatment options and treatment order in patients with HR-positive advanced breast cancer...
January 2016: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
https://www.readbyqxmd.com/read/26793003/pi3k-inhibitors-as-new-cancer-therapeutics-implications-for-clinical-trial-design
#16
REVIEW
Cristian Massacesi, Emmanuelle Di Tomaso, Patrick Urban, Caroline Germa, Cornelia Quadt, Lucia Trandafir, Paola Aimone, Nathalie Fretault, Bharani Dharan, Ranjana Tavorath, Samit Hirawat
The PI3K-AKT-mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/26510854/inhibiting-the-pi3k-signaling-pathway-buparlisib-as-a-new-targeted-option-in-breast-carcinoma
#17
REVIEW
L G Estévez, E García, M Hidalgo
Aberrations in the PI3K signaling pathway are frequently observed in patients with breast cancer. Because of that, PI3K inhibitors are attractive options for the treatment of breast cancer because PI3K is the most proximal component of the pathway other than receptor tyrosine kinases. Buparlisib is a potent and highly specific oral pan-class I PI3K inhibitor, which is currently under investigation in patients with breast cancer. In this article, we describe the PI3K signaling pathway, the prognostic value of PI3K pathway mutations, as well as the mechanism of action of buparlisib...
June 2016: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/26402468/evaluation-of-in-vitro-activity-of-the-class-i-pi3k-inhibitor-buparlisib-bkm120-in-pediatric-bone-and-soft-tissue-sarcomas
#18
Jennifer L Anderson, Ann Park, Ryan Akiyama, William D Tap, Christopher T Denny, Noah Federman
Pediatric bone and soft tissue sarcomas often display increased Akt phosphorylation through up regulation of insulin-like growth factor (IGF1) signaling. Additionally, Akt signaling has been linked to resistance to IGF1 receptor (IGF1R) and mTOR (mammalian target of rapamycin) inhibitors in sarcoma, further demonstrating the role of Akt in tumor survival. This suggests targeting components of the PI3K/Akt pathway may be an effective therapeutic strategy. Here, we investigated the in vitro activity of the pan-class I PI3K inhibitor buparlisib (BKM120) in pediatric bone and soft tissue sarcomas...
2015: PloS One
https://www.readbyqxmd.com/read/26183800/a-phase-1-open-label-single-dose-study-of-the-pharmacokinetics-of-buparlisib-in-subjects-with-mild-to-severe-hepatic-impairment
#19
Denes Csonka, Katharine Hazell, Edward Waldron, Sebastien Lorenzo, Vincent Duval, Lucia Trandafir, Zhanna D Kobalava
The pharmacokinetics (PK) and safety of single-dose buparlisib (30 mg) were assessed in subjects with mild to severe hepatic impairment (n = 6 each) relative to healthy controls (n = 13). Blood samples were collected until 336 hours postdose and evaluated by liquid chromatography tandem mass spectrometry. PK parameters (including area under the curve [AUC∞ ] and Cmax ) were derived using noncompartmental analysis. Buparlisib was rapidly absorbed in all groups (median Tmax 1.0-1.3 h). Buparlisib exposure (AUC∞ ) was moderately increased in subjects with mild (geometric mean ratio [GMR] 1...
March 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/26098748/safety-and-efficacy-of-buparlisib-bkm120-in-patients-with-pi3k-pathway-activated-non-small-cell-lung-cancer-results-from-the-phase-ii-basalt-1-study
#20
Johan F Vansteenkiste, Jean-Luc Canon, Filippo De Braud, Francesco Grossi, Tommaso De Pas, Jhanelle E Gray, Wu-Chou Su, Enriqueta Felip, Hiroshige Yoshioka, Cesare Gridelli, Grace K Dy, Sumitra Thongprasert, Martin Reck, Paola Aimone, Gena Atalla Vidam, Pantelia Roussou, Ying A Wang, Emmanuelle Di Tomaso, Jean-Charles Soria
INTRODUCTION: The phosphatidylinositol 3-kinase (PI3K) pathway promotes tumor growth and treatment resistance in non-small cell lung cancer (NSCLC). The aim of the open-label, two-stage, Phase II study BASALT-1 (NCT01820325) was to investigate the pan-PI3K inhibitor buparlisib (BKM120) in patients with PI3K pathway-activated, relapsed NSCLC. METHODS: After prescreening for PI3K pathway activation, patients with PI3K pathway-activated, metastatic, squamous or nonsquamous NSCLC, who had relapsed after prior systemic antineoplastic therapy, were enrolled...
September 2015: Journal of Thoracic Oncology
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