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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
#1
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...
March 3, 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
#2
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
#3
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/28230287/therapeutic-potential-of-targeting-pi3k-akt-pathway-in-treatment-of-colorectal-cancer-rational-and-progress
#4
Afsane Bahrami, Majid Khazaei, Malihe Hasanzadeh, Soodabeh ShahidSales, Mona Joudi Mashhad, Marjaneh Farazestanian, Hamid Reza Sadeghnia, Majid Rezayi, Mina Maftouh, Seyed Mahdi Hassanian, Amir Avan
PI3K/AKT/mTOR signaling pathway is one of the key dysregulated pathways in different tumor types, including colorectal cancer (CRC). Activation of this pathway is shown to be related with cellular transformation, tumor progression, cell survival and drug resistance. There is growing body of data evaluating the value of PI3K/AKT/mTOR inhibitors in CRC (e.g., BEZ235, NVP-BEZ235, OSI-027, everolimus, MK-2206, KRX-0401, BYL719 and BKM120). This report summarizes the current knowledge about PI3K/AKT pathway and its cross talk with ERK/MAPK and mTOR pathways with particular emphasis on the value of targeting this pathway as a potential therapeutic target in treatment of colorectal cancer...
February 23, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28119806/class-i-phosphatidylinositol-3-kinase-inhibitors-for-cancer-therapy
#5
REVIEW
Wennan Zhao, Yuling Qiu, Dexin Kong
The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers. Class I PI3Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin (mTOR) to play key roles in carcinogenesis. Therefore, PI3K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3K inhibitors...
January 2017: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/28119490/in-vitro-and-in-vivo-synergistic-antitumor-activity-of-the-combination-of-bkm120-and-erlotinib-in-head-and-neck-cancer-mechanism-of-apoptosis-and-resistance
#6
Abu Syed Md Anisuzzaman, Abedul Haque, Dongsheng Wang, Mohammad Aminur Rahman, Chao Zhang, Zhengjia Chen, Zhuo Georgia Chen, Dong M Shin, A R M Ruhul Amin
We previously reported that the EGFR-targeted inhibitor erlotinib induces G1 arrest of SCCHN cell lines without inducing significant apoptosis. Large-scale genomic studies suggest that >50% of SCCHN cases have activation of PI3K pathways. This study investigated whether co-targeting of EGFR and PI3K has synergistic antitumor effects and apoptosis induction. We examined growth suppression, apoptosis, and signaling pathway modulation resulting from single and combined targeting of EGFR and PI3K with erlotinib and BKM120, respectively, in a panel of SCCHN cell lines and a xenograft model of SCCHN...
January 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28119489/pi3k-inhibitors-synergize-with-fgfr-inhibitors-to-enhance-antitumor-responses-in-fgfr2-mutant-endometrial-cancers
#7
Leisl Packer, Xinyan Geng, Vanessa F Bonazzi, Robert Ju, Clare Mahon, Margaret C Cummings, Sally-Anne Stephenson, Pamela M Pollock
Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer (EC). ECs display hyper-activation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such as FGFR2, KRAS, PTEN, PIK3CA and PIK3R1. FGFR2, as well as the PI3K pathway, have emerged as potential therapeutic targets in EC. Activation of the PI3K pathway is seen in >90% of FGFR2mutant ECs. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719...
January 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28108151/a-functional-genetic-screen-identifies-the-phosphoinositide-3-kinase-pathway-as-a-determinant-of-resistance-to-fibroblast-growth-factor-receptor-inhibitors-in-fgfr-mutant-urothelial-cell-carcinoma
#8
Liqin Wang, Tonći Šuštić, Rodrigo Leite de Oliveira, Cor Lieftink, Pasi Halonen, Marieke van de Ven, Roderick L Beijersbergen, Michel M van den Heuvel, René Bernards, Michiel S van der Heijden
Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation)...
January 17, 2017: European Urology
https://www.readbyqxmd.com/read/28092667/oncogenic-braf-fusions-in-mucosal-melanomas-activate-the-mapk-pathway-and-are-sensitive-to-mek-pi3k-inhibition-or-mek-cdk4-6-inhibition
#9
H S Kim, M Jung, H N Kang, H Kim, C-W Park, S-M Kim, S J Shin, S H Kim, S G Kim, E K Kim, M R Yun, Z Zheng, K Y Chung, J Greenbowe, S M Ali, T-M Kim, B C Cho
Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated...
January 16, 2017: Oncogene
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
#10
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 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
#11
Hyun-Jung Kim, Soo Yoon Lee, Chan Young Kim, Yun Hwan Kim, Woong Ju, Seung Cheol 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)...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28004037/differential-compensation-mechanisms-define-resistance-to-pi3k-inhibitors-in-pik3ca-amplified-hnscc
#12
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
#13
Jiqing Sai, Philip Owens, Sergey V Novitskiy, 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
#14
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...
January 31, 2017: 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
#15
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
#16
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
#17
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
#18
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...
November 15, 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
#19
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
#20
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
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