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Denis Soulières, Lisa Lictira, Ricard Mesía, Éva Remenár, Shau-Hsuan Li, Andrey Karpenko, Marie Chol, Ying A Wang, Nadia Solovieff, Laurence Bourdeau, Dalila Sellami, Sandrine Faivre
PURPOSE: The preplanned exploratory analysis of the BERIL-1 trial presented here aimed to identify biomarkers of response to the combination of buparlisib and paclitaxel. PATIENTS AND METHODS: BERIL-1 was a multicenter, randomized, double-blind, placebo-controlled phase 2 study. Patients with recurrent or metastatic SCCHN progressing on/after one previous platinum-based chemotherapy regimen in the recurrent or metastatic setting were treated with either buparlisib plus paclitaxel or placebo plus paclitaxel...
February 28, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Filip Mundt, Sandeep Rajput, Shunqiang Li, Kelly V Ruggles, Arshag D Mooradian, Philipp Mertins, Michael A Gillette, Karsten Krug, Zhanfang Guo, Jeremy Hoog, Petra Erdmann-Gilmore, Tina Primeau, Shixia Huang, Dean P Edwards, Xiaowei Wang, Xuya Wang, Emily Kawaler, D R Mani, Karl R Clauser, Feng Gao, Jingqin Luo, Sherri R Davies, Gary L Johnson, Kuan-Lin Huang, Christopher J Yoon, Li Ding, David Fenyö, Matthew J Ellis, R Reid Townsend, Jason M Held, Steven A Carr, Cynthia X Ma
Activation of phosphoinositide 3-kinase (PI3K) signaling is frequently observed in triple-negative breast cancer (TNBC), yet PI3K inhibitors have shown limited clinical activity. To investigate intrinsic and adaptive mechanisms of resistance, we analyzed a panel of patient-derived xenograft models of TNBC with varying responsiveness to buparlisib, a pan-PI3K inhibitor. In a subset of patient-derived xenografts, resistance was associated with incomplete inhibition of PI3K signaling and upregulated MAPK/MEK signaling in response to buparlisib...
February 22, 2018: Cancer Research
Carmen Criscitiello, Giulia Viale, Giuseppe Curigliano, Aron Goldhirsch
Alteration of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin signaling pathway is key for the growth and survival of several cancers, including breast cancer. In addition, dysregulation of PI3K signaling may contribute to resistance to several anticancer agents. PI3K inhibitors may, therefore, be effective as antineoplastic therapy. Buparlisib is a potent and highly specific oral inhibitor of the pan-class I PI3K family. Buparlisib specifically inhibits class I PIK3 in the PI3K/AKT kinase signaling pathway in an ATP-competitive manner, thus inhibiting the production of the secondary messenger phosphatidylinositol (3,4,5)-trisphosphate and activation of the PI3K signaling pathway...
2018: Breast Cancer: Targets and Therapy
Siva Sankar Murthy Bandaru, Shatrughn Bhilare, Nicolas Chrysochos, Vijay Gayakhe, Ivan Trentin, Carola Schulzke, Anant R Kapdi
A mild and highly efficient catalytic amination procedure for chloroheteroarenes at ambient temperature using the Pd/PTABS catalytic system is reported. The protocol is selective for the amination of chloroheteroarenes using secondary amines such as piperidine, pyrrolidine, and several others. The exceptional mildness of the developed protocol is beneficial for the synthesis of a crucial Buparlisib intermediate as well as the formal synthesis of Alogliptin in competitive yields.
January 5, 2018: Organic Letters
Angelo Di Leo, Stephen Johnston, Keun Seok Lee, Eva Ciruelos, Per E Lønning, Wolfgang Janni, Ruth O'Regan, Marie-Ange Mouret-Reynier, Dimitar Kalev, Daniel Egle, Tibor Csőszi, Roberto Bordonaro, Thomas Decker, Vivianne C G Tjan-Heijnen, Sibel Blau, Alessio Schirone, Denis Weber, Mona El-Hashimy, Bharani Dharan, Dalila Sellami, Thomas Bachelot
BACKGROUND: Activation of the PI3K/AKT/mTOR pathway occurs frequently in breast cancer that is resistant to endocrine therapy. Approved mTOR inhibitors effectively inhibit cell growth and proliferation but elicit AKT phosphorylation via a feedback activation pathway, potentially leading to resistance to mTOR inhibitors. We evaluated the efficacy and safety of buparlisib plus fulvestrant in patients with advanced breast cancer who were pretreated with endocrine therapy and mTOR inhibitors...
January 2018: Lancet Oncology
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...
April 2018: Breast Cancer Research and Treatment
Duy Cong Tran, Ann Moffat, Richard Brotherton, Alana Pague, Gefei Alex Zhu, Anne Lynn S Chang
No abstract text is available yet for this article.
November 23, 2017: Journal of the American Academy of Dermatology
Marie Robert, Jean-Sébastien Frenel, Emmanuelle Bourbouloux, Dominique Berton Rigaud, Anne Patsouris, Paule Augereau, Carole Gourmelon, Mario Campone
Breast cancer is the most frequent cancer in women. Despite a decline in breast cancer mortality, prognosis of advanced breast cancer remains poor. In a desperate need to improve breast cancer outcomes, newer agents that target molecular pathways are being tested. Deregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) is frequently found in breast cancer. This can lead to resistance of endocrine therapy and anti-HER2 therapies. Targeting this pathway may restore sensitivity to these compounds...
December 2017: Expert Opinion on Pharmacotherapy
Autumn J McRee, Paul K Marcom, Dominic T Moore, William C Zamboni, Zachary A Kornblum, Zhiyuan Hu, Rachel Phipps, Carey K Anders, Katherine Reeder-Hayes, Lisa A Carey, Karen E Weck, Charles M Perou, E Claire Dees
BACKGROUND: Buparlisib is an oral pan-class I phosphotidyinositol-3-kinase (PI3K) inhibitor. The present phase I study evaluated the safety, pharmacokinetics, and efficacy of buparlisib with capecitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients received buparlisib once daily (range, 50 to 100 mg) for 3 weeks with capecitabine twice daily (range, 1000 to 1250 mg/m(2)) for 2 weeks with a 1-week break. Dose escalation used a traditional "3 + 3" design with standard definitions of dose-limiting toxicity (DLT) and maximum tolerated dose...
October 28, 2017: Clinical Breast Cancer
Wenlu Li, Qinsheng Sun, Lu Song, Chunmei Gao, Feng Liu, Yuzong Chen, Yuyang Jiang
PI3K/Akt/mTOR and hedgehog (Hh) signalings are two important pathways in breast cancer, which are usually connected with the drug resistance and cancer migration. Many studies indicated that PI3K/Akt/mTOR inhibitors and Hh inhibitors displayed synergistic effects, and the combination of the two signaling drugs could delay drug resistance and inhibit cancer migration in breast cancer. Therefore, the development of molecules simultaneously inhibiting these two pathways is urgent needed. Based on the structures of PI3K inhibitor buparlisib and Hh inhibitor vismodegib, a series of hybrid structures were designed and synthesized utilizing rational drug design and computer-based drug design...
December 1, 2017: European Journal of Medicinal Chemistry
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
Activation of the phosphatidylinositol 3-kinase/mechanistic target of rapamycin pathway plays a role in the pathogenesis of non-Hodgkin lymphoma. This multicenter, open-label phase 2 study evaluated buparlisib (BKM120), a pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or refractory non-Hodgkin lymphoma. Three separate cohorts of patients (with diffuse large B-cell lymphoma, mantle cell lymphoma, or follicular lymphoma) received buparlisib 100 mg once daily until progression, intolerance, or withdrawal of consent...
December 2017: Haematologica
Mathilde Guerin, Keyvan Rezai, Nicolas Isambert, Mario Campone, Aurélie Autret, Jihane Pakradouni, Magali Provansal, Jacques Camerlo, Renaud Sabatier, François Bertucci, Emmanuelle Charafe-Jauffret, Alice Hervieu, Jean-Marc Extra, Patrice Viens, François Lokiec, Jean-Marie Boher, Anthony Gonçalves
BACKGROUND: Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms. PATIENTS AND METHODS: PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer...
November 2017: European Journal of Cancer
Pawel Robak, Tadeusz Robak
Over the last few years, several new synthetic drugs, particularly Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K) and BCL-2 inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL). Areas covered: This review highlights key aspects of BTK, PI3K and BCL-2 inhibitors that are currently at various stages of preclinical and clinical development in CLL. A literature review of the MEDLINE database for articles in English concerning CLL, B-cell receptor, BCL-2 antagonists, BTK inhibitors and PI3K inhibitors, was conducted via PubMed...
November 2017: Expert Opinion on Investigational Drugs
Sibylle Loibl, Lorena de la Pena, Valentina Nekljudova, Dimitrios Zardavas, Stefan Michiels, Carsten Denkert, Mahdi Rezai, Begoña Bermejo, Michael Untch, Soo Chin Lee, Sabine Turri, Patrick Urban, Sherko Kümmel, Guenther Steger, Andrea Gombos, Michael Lux, Martine J Piccart, Gunter Von Minckwitz, José Baselga, Sherene Loi
AIM: The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer. METHODS: NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel...
November 2017: European Journal of Cancer
Andrea Cavazzoni, Silvia La Monica, Roberta Alfieri, Andrea Ravelli, Nele Van Der Steen, Rocco Sciarrillo, Denise Madeddu, Costanza Anna Maria Lagrasta, Federico Quaini, Mara Bonelli, Claudia Fumarola, Daniele Cretella, Graziana Digiacomo, Marcello Tiseo, Godefridus J Peters, Andrea Ardizzoni, Pier Giorgio Petronini, Elisa Giovannetti
Squamous cell lung carcinoma (SCC) accounts for 30% of patients with NSCLC and to date, no molecular targeted agents are approved for this type of tumor. However, recent studies have revealed several oncogenic mutations in SCC patients, including an alteration of the PI3K/AKT pathway, i.e. PI3K point mutations and amplification, AKT mutations and loss or reduced PTEN expression. Prompted by our observation of a correlation between PTEN loss and FAK phosphorylation in a cohort of patients with stage IV SCC, we evaluated the relevance of PTEN loss in cancer progression as well as the efficacy of a new combined treatment with the pan PI3K inhibitor buparlisip and the FAK inhibitor defactinib...
August 8, 2017: Oncotarget
I-Chun Chen, Li-Ping Hsiao, I-Wen Huang, Huei-Chieh Yu, Ling-Chun Yeh, Ching-Hung Lin, Tom Wei-Wu Chen, Ann-Lii Cheng, Yen-Shen Lu
Tamoxifen is the standard first-line hormonal therapy for premenopausal women with estrogen receptor (ER)-positive metastatic breast cancer (BC). One of the crucial mechanisms underlying hormonal therapy resistance is the collateral activation of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We explored whether PI3K inhibitors, buparlisib and alpelisib, enhance the efficacy of tamoxifen against ER-positive BC cells. We have observed a synergism between alpelisib or buparlisib and tamoxifen in the treatment for ER-positive BC cell lines harboring different PI3K alterations...
August 29, 2017: Scientific Reports
S Degryse, C E de Bock, S Demeyer, I Govaerts, S Bornschein, D Verbeke, K Jacobs, S Binos, D A Skerrett-Byrne, H C Murray, N M Verrills, P Van Vlierberghe, J Cools, M D Dun
Mutations in the interleukin-7 receptor (IL7R) or the JAK3 kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here, we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib...
August 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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
Simon Peter Gampenrieder, Gabriel Rinnerthaler, Richard Greil
At the 2016 San Antonio Breast Cancer Symposium, several interesting phase II and phase III studies investigating systemic therapies for metastatic breast cancer were presented. The PrEGOC 0102 trial demonstrated that the combination of fulvestrant plus everolimus is safe and effective and could be an alternative to exemestane plus everolimus for selected patients with hormone-receptor positive, HER2-negative disease. The pan-PI3K inhibitor buparlisib showed some activity in combination with fulvestrant after failure of everolimus in the BELLE-3 trial...
2017: Memo
Mark R Nathan, Peter Schmid
Fulvestrant is a selective estrogen receptor degrader that binds, blocks and degrades the estrogen receptor (ER), leading to complete inhibition of estrogen signaling through the ER. This review article further explains the mechanism of action of the drug and goes on to review the trials carried out to optimize its dosing. Multiple trials have been undertaken to compare fulvestrant with other endocrine treatments, and results have shown it to have similar efficacy to anastrozole, tamoxifen and exemestane at 250 mg every 28 days...
2017: Oncology and Therapy
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