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https://www.readbyqxmd.com/read/28923573/neoadjuvant-buparlisib-plus-trastuzumab-and-paclitaxel-for-women-with-her2-primary-breast-cancer-a-randomised-double-blind-placebo-controlled-phase-ii-trial-neophoebe
#1
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...
September 15, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28881794/enhanced-efficacy-of-akt-and-fak-kinase-combined-inhibition-in-squamous-cell-lung-carcinomas-with-stable-reduction-in-pten
#2
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
https://www.readbyqxmd.com/read/28852212/phosphatidylinositol-3-kinase-inhibitors-buparlisib-and-alpelisib-sensitize-estrogen-receptor-positive-breast-cancer-cells-to-tamoxifen
#3
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
https://www.readbyqxmd.com/read/28852199/mutant-jak3-phosphoproteomic-profiling-predicts-synergism-between-jak3-inhibitors-and-mek-bcl2-inhibitors-for-the-treatment-of-t-cell-acute-lymphoblastic-leukemia
#4
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
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
#5
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 1, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28725277/sabcs-2016-systemic-therapy-for-metastatic-breast-cancer
#6
REVIEW
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
https://www.readbyqxmd.com/read/28680952/a-review-of-fulvestrant-in-breast-cancer
#7
REVIEW
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
https://www.readbyqxmd.com/read/28649657/dual-pi3k-and-wnt-pathway-inhibition-is-a-synergistic-combination-against-triple-negative-breast-cancer
#8
Jeffrey P Solzak, Rutuja V Atale, Bradley A Hancock, Anthony L Sinn, Karen E Pollok, David R Jones, Milan Radovich
Triple negative breast cancer accounts for 15-20% of all breast cancer cases, but despite its lower incidence, contributes to a disproportionately higher rate of mortality. As there are currently no Food and Drug Administration-approved targeted agents for triple negative breast cancer, we embarked on a genomic-guided effort to identify novel targeted modalities. Analyses by our group and The Cancer Genome Atlas have identified activation of the PI3K-pathway in the majority of triple negative breast cancers...
2017: NPJ Breast Cancer
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
#9
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/28596475/enhanced-efficacy-of-akt-and-fak-kinase-combined-inhibition-in-squamous-cell-lung-carcinomas-with-stable-reduction-in-pten
#10
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...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28576675/buparlisib-plus-fulvestrant-versus-placebo-plus-fulvestrant-in-postmenopausal-hormone-receptor-positive-her2-negative-advanced-breast-cancer-belle-2-a-randomised-double-blind-placebo-controlled-phase-3-trial
#11
RANDOMIZED CONTROLLED TRIAL
José Baselga, Seock-Ah Im, Hiroji Iwata, Javier Cortés, Michele De Laurentiis, Zefei Jiang, Carlos L Arteaga, Walter Jonat, Mark Clemons, Yoshinori Ito, Ahmad Awada, Stephen Chia, Agnieszka Jagiełło-Gruszfeld, Barbara Pistilli, Ling-Ming Tseng, Sara Hurvitz, Norikazu Masuda, Masato Takahashi, Peter Vuylsteke, Soulef Hachemi, Bharani Dharan, Emmanuelle Di Tomaso, Patrick Urban, Cristian Massacesi, Mario Campone
BACKGROUND: Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. METHODS: The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study...
July 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28537878/biological-characterization-of-sn32976-a-selective-inhibitor-of-pi3k-and-mtor-with-preferential-activity-to-pi3k%C3%AE-in-comparison-to-established-pan-pi3k-inhibitors
#12
Gordon W Rewcastle, Sharada Kolekar, Christina M Buchanan, Swarna A Gamage, Anna C Giddens, Kit Y Tsang, Jackie D Kendall, Ripudaman Singh, Woo-Jeong Lee, Greg C Smith, Weiping Han, David J Matthews, William A Denny, Peter R Shepherd, Stephen M F Jamieson
Multiple therapeutic agents have been developed to target the phosphatidylinositol 3-kinase (PI3K) signaling pathway, which is frequently dysregulated in cancer promoting tumor growth and survival. These include pan PI3K inhibitors, which target class Ia PI3K isoforms and have largely shown limited single agent activity with narrow therapeutic windows in clinical trials. Here, we characterize SN32976, a novel pan PI3K inhibitor, for its biochemical potency against PI3K isoforms and mTOR, kinase selectivity, cellular activity, pharmacokinetics, pharmacodynamics and antitumor efficacy relative to five clinically-evaluated pan PI3K inhibitors: buparlisib, dactolisib, pictilisib, omipalisib and ZSTK474...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28502694/phase-ii-trial-of-the-pi3-kinase-inhibitor-buparlisib-bkm-120-with-or-without-enzalutamide-in-men-with-metastatic-castration-resistant-prostate-cancer
#13
MULTICENTER STUDY
Andrew J Armstrong, Susan Halabi, Patrick Healy, Joshi J Alumkal, Carolyn Winters, Julie Kephart, Rhonda L Bitting, Carey Hobbs, Colleen F Soleau, Tomasz M Beer, Rachel Slottke, Kelly Mundy, Evan Y Yu, Daniel J George
BACKGROUND: Phosphatidylinositol-3-kinase (PI3K) and androgen receptor pathway activation is common in metastatic castration resistant prostate cancer (mCRPC). Buparlisib is an oral, pan-class I PI3 kinase inhibitor. METHODS: This was a multisite single arm phase II trial of buparlisib 100 mg ± enzalutamide daily in men with mCRPC whose disease progressed on or who were not candidates for docetaxel. The primary end-point was the rate of radiographic/clinical progression-free survival (PFS) at 6 months...
August 2017: European Journal of Cancer
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
#14
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...
May 9, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28396358/extracellular-matrix-integrin-signaling-promotes-resistance-to-combined-inhibition-of-her2-and-pi3k-in-her2-breast-cancer
#15
Ariella B Hanker, Mónica Valeria Estrada, Giampaolo Bianchini, Preston D Moore, Junfei Zhao, Feixiong Cheng, James P Koch, Luca Gianni, Darren R Tyson, Violeta Sánchez, Brent N Rexer, Melinda E Sanders, Zhongming Zhao, Thomas P Stricker, Carlos L Arteaga
PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2(+)/PIK3CA(H1047R) transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treating HER2(+)/PIK3CA(H1047R) tumor-bearing mice long term with the drug combination. RNA sequencing of TPB-resistant tumors revealed that extracellular matrix and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin β1/Src...
June 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28282611/phase-ib-dose-finding-study-of-abiraterone-acetate-plus-buparlisib-bkm120-or-dactolisib-bez235-in-patients-with-castration-resistant-prostate-cancer
#16
Christophe Massard, Kim Nguyen Chi, Daniel Castellano, Johann de Bono, Gwenaelle Gravis, Luc Dirix, Jean-Pascal Machiels, Alain Mita, Begona Mellado Gonzalez, Sabine Turri, Joan Maier, Denes Csonka, Arunava Chakravartty, Karim Fizazi
BACKGROUND: The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signalling axis and androgen receptor (AR) pathways exhibit reciprocal feedback regulation in phosphatase and tensin homologue (PTEN)-deficient metastatic castration-resistant prostate cancer (CRPC) in preclinical models. This phase Ib study evaluated the pan-PI3K inhibitor buparlisib (BKM120) and the dual pan-PI3K/ mammalian target of rapamycin (mTOR) inhibitor dactolisib (BEZ235) in combination with abiraterone acetate (AA) in patients with CRPC...
May 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28281183/a-phase-1b-dose-expansion-study-of-the-pan-class-i-pi3k-inhibitor-buparlisib-bkm120-plus-carboplatin-and-paclitaxel-in-pten-deficient-tumors-and-with-dose-intensified-carboplatin-and-paclitaxel
#17
Lillian M Smyth, Kelsey R Monson, Komal Jhaveri, Alexander Drilon, Bob T Li, Wassim Abida, Gopa Iyer, John F Gerecitano, Mrinal Gounder, James J Harding, Martin H Voss, Vicky Makker, Alan L Ho, Pedram Razavi, Alexia Iasonos, Philip Bialer, Mario E Lacouture, Jerrold B Teitcher, Joseph P Erinjeri, Nora Katabi, Matthew G Fury, David M Hyman
Purpose We previously reported the phase I dose escalation study of buparlisib, a pan-class 1A PI3K inhibitor, combined with platinum/taxane-based chemotherapy in patients with advanced solid tumors. The combination was well tolerated and promising preliminary efficacy was observed in PTEN deficient tumors. This phase I dose expansion study now evaluates buparlisib plus high dose carboplatin and paclitaxel in unselected patients with advanced solid tumors and buparlisib plus standard dose carboplatin and paclitaxel in patients with PTEN deficient tumors (ClinicalTrials...
March 9, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28276440/deconvolution-of-buparlisib-s-mechanism-of-action-defines-specific-pi3k-and-tubulin-inhibitors-for-therapeutic-intervention
#18
Thomas Bohnacker, Andrea E Prota, Florent Beaufils, John E Burke, Anna Melone, Alison J Inglis, Denise Rageot, Alexander M Sele, Vladimir Cmiljanovic, Natasa Cmiljanovic, Katja Bargsten, Amol Aher, Anna Akhmanova, J Fernando Díaz, Doriano Fabbro, Marketa Zvelebil, Roger L Williams, Michel O Steinmetz, Matthias P Wymann
BKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from BKM120 by only one atom. We show that these minute changes separate the dual activity of BKM120 into discrete PI3K and tubulin inhibitors. Analysis of the compounds cellular growth arrest phenotypes and microtubule dynamics suggest that the antiproliferative activity of BKM120 is mainly due to microtubule-dependent cytotoxicity rather than through inhibition of PI3K...
March 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28195237/head-and-neck-cancer-buparlisib-is-an-effective-second-line-treatment
#19
Peter Sidaway
No abstract text is available yet for this article.
April 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28166090/chemotherapy-for-recurrent-metastatic-head-and-neck-cancers
#20
Andy Karabajakian, Philippe Toussaint, Eve-Marie Neidhardt, Valérie Paulus, Pierre Saintigny, Jérôme Fayette
Chemotherapy is the only option of treatment for most patients presenting with a recurrent and/or metastatic head and neck squamous cell carcinoma. The triple association of cisplatin, 5-fluorouracile, and cetuximab is still the current standard for fit patients. Other schemes are currently being compared with this protocol in ongoing trials and the association of cisplatin, docetaxel, and cetuximab appears to be the most efficient. The human papilloma virus is very likely a favorable prognostic factor. Immunotherapy with nivolumab or pembrolizumab is now a new standard of treatment in second line after yielding an improvement in overall survival, but predictive markers of efficacy are needed to refine the selection of patients...
April 2017: Anti-cancer Drugs
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