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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
Chen Zhang, Bingfei Xu, Pian Liu
Breast cancer is one of the leading causes of death for women worldwide. Among various subtypes of breast cancer, human epidermal growth factor receptor 2 (HER2)-positive and phosphatase and tensin homolog (PTEN) loss breast cancer is a cause of great concern in terms of its resistance to HER2-targeted therapies and its poor prognosis. Phosphatidylinositol 3-kinase (PI3K)/AKT hyperphosphorylation is considered one of key mechanisms leading to this resistance, thus combination therapy of PI3K inhibitors and HER2 antibodies is promising for overcoming this problem, and more specific regimens should be designed in this age of precision medicine...
September 17, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Rajani Kanteti, Jacob J Riehm, Immanuel Dhanasingh, Frances E Lennon, Tamara Mirzapoiazova, Bolot Mambetsariev, Hedy L Kindler, Ravi Salgia
Malignant pleural mesothelioma (MPM) is an aggressive cancer that is commonly associated with prior asbestos exposure. Receptor tyrosine kinases (RTKs) such as MET and its downstream target PI3K are overexpressed and activated in a majority of MPMs. Here, we studied the combinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K inhibitor, BKM120, or with a PI3K/mTOR dual inhibitor, GDC-0980, in mesothelioma. Cell viability results showed that MPM cells were highly sensitive to crizotinib, BKM120 and GDC-0980 when used individually and their combination was more effective in suppressing growth...
2016: Scientific Reports
Davood Bashash, Ava Safaroghli-Azar, Mahda Delshad, Samaneh Bayati, Elaheh Nooshinfar, Seyed H Ghaffari
Complex interplay of intracellular signaling networks, spanning from the extracellular environment to the nucleus, orchestrate normal cell growth and survival. Dysregulation of such signals contributes to malignant transformation, thereby giving the cancer cells a survival advantage, but also could be exploited for new anticancer interventions. The aim of this study was to investigate the effects of pan class-I PI3K inhibitor NVP-BKM120 on two distinct acute leukemia cell lines, NB4 (with mutant p53) and Nalm-6 (with wild-type p53)...
October 2016: International Journal of Biochemistry & Cell Biology
Hui Ren, Hua Guo, Asmitananda Thakur, Shuo Zhang, Ting Wang, Yiqian Liang, Puyu Shi, Lei Gao, Feng Liu, Jing Feng, Tianjun Chen, Tian Yang, Dong Shang, Johnson J Liu, Feng Xu, Mingwei Chen
NVP-BKM120 (BKM120) is a new pan-class I phosphatidylinositol-3 kinase (PI3K) inhibitor and has been tested in clinical trials as an anticancer agent. In this study, we determined whether BKM120 induces autophagy and the impact of autophagy induction on BKM120's growth-inhibitory activity. BKM120 potently induced elevation of autophagosome-bound type II LC3 (LC3-II) protein, predominantly in cell lines insensitive to BKM120, thereby inducing autophagy. The presence of lysosomal protease inhibitor chloroquine further enhanced the levels of LC3-II...
August 27, 2016: Oncotarget
Z Zelenko, E J Gallagher, A Tobin-Hess, V Belardi, R Rostoker, J Blank, Y Dina, D LeRoith
Increased breast cancer risk and mortality has been associated with obesity and type 2 diabetes (T2D). Hyperinsulinemia, a key factor in obesity, pre-diabetes and T2D, has been associated with decreased breast cancer survival. In this study, a mouse model of pre-diabetes (MKR mouse) was used to investigate the mechanisms through which endogenous hyperinsulinemia promotes mammary tumor metastases. The MKR mice developed larger primary tumors and greater number of pulmonary metastases compared with wild-type (WT) mice after injection with c-Myc/Vegf overexpressing MVT-1 cells...
August 29, 2016: Oncogene
W L Zhang, W J Ma, S Chen, X Z Wu, H R Zhang, J H Zhang
OBJECTIVE: To explore the molecular mechanisms of resistance to phosphatidyl inositol 3-kinase (PI3K) inhibitors in triple-negative breast cancer (TNBC) cells. METHODS: HCC70 cells (TNBC) were transfected with siFZD7, siWANT5B or siGSK3 using lipofectamine 2000 transfection reagent. The expression levels of key proteins of WNT/β-catenin and PI3K/AKT/mTOR pathways were determined by Western blot analysis. After HCC70, MCF-7 (ER-positive) and SK-BR3 (HER2-positive) cells were treated with PI3K/AKT/mTOR inhibitors, the inhibition rates of cell proliferation were measured by MTT assay, and half maximal inhibitory concentrations (IC50) were calculated...
August 2016: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
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
Wenjun Yu, Yubao Chen, Rufang Xiang, Wenbin Xu, Yan Wang, Jia Tong, Nan Zhang, Yingli Wu, Hua Yan
Proteasome inhibitor bortezomib has proven efficacy against multiple myeloma. However, bortezomib activates the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway (which is essential to the development of myeloma), often resulting in drug resistance and disease recurrence. The addition of BKM120 significantly enhanced the apoptotic effects of bortezomib in both bortezomib-sensitive and bortezomib-resistant cells. Treatment with bortezomib alone increased the phosphorylation of AKT (P-AKT), whereas the addition of BKM120 markedly downregulated P-AKT in both bortezomib-sensitive and bortezomib-resistant cells...
July 20, 2016: Leukemia & Lymphoma
Dong Wang, Chengbo Li, Yuan Zhang, Min Wang, Nan Jiang, Lin Xiang, Ting Li, Thomas M Roberts, Jean J Zhao, Hailing Cheng, Pixu Liu
OBJECTIVE: Combined inhibition of PI3K and PARP has been shown to be effective in the treatment of preclinical models of breast cancer and prostate cancer independent of BRCA or PIK3CA mutational status. However, the knowledge about this combination treatment in ovarian cancer is limited. The aim of this study was to evaluate the therapeutic effect of PI3K inhibitor BKM120 and PARP inhibitor Olaparib on ovarian cancer cell lines bearing wild-type PIK3CA genes. METHODS: We exposed three wild-type PIK3CA ovarian cancer cell lines to a PI3K inhibitor BKM120 and/or a PARP inhibitor Olaparib...
September 2016: Gynecologic Oncology
Ashish Juvekar, Hai Hu, Sina Yadegarynia, Costas A Lyssiotis, Soumya Ullas, Evan C Lien, Gary Bellinger, Jaekyoung Son, Rosanna C Hok, Pankaj Seth, Michele B Daly, Baek Kim, Ralph Scully, John M Asara, Lewis C Cantley, Gerburg M Wulf
We previously reported that combining a phosphoinositide 3-kinase (PI3K) inhibitor with a poly-ADP Rib polymerase (PARP)-inhibitor enhanced DNA damage and cell death in breast cancers that have genetic aberrations in BRCA1 and TP53. Here, we show that enhanced DNA damage induced by PI3K inhibitors in this mutational background is a consequence of impaired production of nucleotides needed for DNA synthesis and DNA repair. Inhibition of PI3K causes a reduction in all four nucleotide triphosphates, whereas inhibition of the protein kinase AKT is less effective than inhibition of PI3K in suppressing nucleotide synthesis and inducing DNA damage...
July 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
Zhenwei Qiu, Shuangzhu Yue, Jinsheng Chang, Guoxia Wang
Objective To investigate the effect of phosphatidylinositide 3-kinase (PI3K) inhibitor BKM120 on the proliferation and apoptosis of human glioma U251 cells. Methods U251 cells were treated with different concentrations of BKM120 (final concentrations were 1, 5, 20 μmol/L) for 48 hours. The effect of BKM120 on cell proliferation was detected by CCK-8 assay. The apoptosis was detected by annexin V-FITC/PI staining. The protein expressions of Bax and Bcl-2 were detected by Western blotting. Results CCK-8 assay showed that BKM120 inhibited U251 proliferation in a concentration-dependent manner and the maximum inhibitory rate was 78...
July 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
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
Elisa Caiola, Laura Brunelli, Mirko Marabese, Massimo Broggini, Monica Lupi, Roberta Pastorelli
KRAS mutations in non-small-cell lung cancer (NSCLC) patients are considered a negative predictive factor and indicate poor response to anticancer treatments. KRAS mutations lead to activation of the PI3K/akt/mTOR pathway, whose inhibition remains a challenging clinical target. Since the PI3K/akt/mTOR pathway and KRAS oncogene mutations all have roles in cancer cell metabolism, we investigated whether the activity of PI3K/akt/mTOR inhibitors (BEZ235 and BKM120) in cells harboring different KRAS status is related to their metabolic effect...
June 6, 2016: Oncotarget
Charlotte M Huijts, Saskia J Santegoets, Maria Quiles Del Rey, Richard R de Haas, Henk M Verheul, Tanja D de Gruijl, Hans J van der Vliet
The PI3K/mTOR pathway is commonly deregulated in cancer. mTOR inhibitors are registered for the treatment of several solid tumors and novel inhibitors are explored clinically. Notably, this pathway also plays an important role in immunoregulation. While mTOR inhibitors block cell cycle progression of conventional T cells (Tconv), they also result in the expansion of CD4(+)CD25(hi)FOXP3(+) regulatory T cells (Tregs), and this likely limits their clinical antitumor efficacy. Here, we compared the effects of dual mTOR/PI3K inhibition (using BEZ235) to single PI3K (using BKM120) or mTOR inhibition (using rapamycin and everolimus) on Treg expansion and functionality...
July 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Feng Yu, Jing Zhao, Yunhui Hu, Yang Zhou, Rong Guo, Jingchao Bai, Sheng Zhang, Huilai Zhang, Jin Zhang
Deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway is common in breast cancer and is frequently associated with resistance to both traditional chemotherapy and targeted drugs. There is a growing body of evidence indicating that a small subpopulation of self-renewing cells, the so called cancer stem cells (CSC), are responsible for the growth of drug resistant secondary tumors. As many CSCs have upregulated the PI3K/Akt signalling pathway, preclinical and clinical studies are addressing the inhibition of this axis to target drug resistance...
July 2016: Oncology Reports
Ze-Bo Jiang, Jun Huang, Chun Xie, Xia Li, Liping Liu, Jiaxi He, Hui Pan, Liyan Huang, Xing-Xing Fan, Xiao-Jun Yao, Ying Xie, Na Li, Liang Liu, Jian-Xing He, Elaine Lai-Han Leung
EGFR and KRAS mutations are the two most common driver mutations in non-small cell lung cancer (NSCLC). Molecular target-based therapy using small molecules such as gefitinib has been used for inhibiting EGFR with good initial responses; however, drug resistance is common when using a mono-targeting strategy. At present, KRAS remains an undruggable target. As such, the development of new drugs targeting the downstream of KRAS and EGFR and their crosstalk pathways is critically needed to effectively treat NSCLC...
July 2016: Oncology Reports
Beatrice Bissig-Choisat, Claudia Kettlun-Leyton, Xavier D Legras, Barry Zorman, Mercedes Barzi, Leon L Chen, Mansi D Amin, Yung-Hsin Huang, Robia G Pautler, Oliver A Hampton, Masand M Prakash, Diane Yang, Malgorzata Borowiak, Donna Muzny, Harsha Vardhan Doddapaneni, Jianhong Hu, Yan Shi, M Waleed Gaber, M John Hicks, Patrick A Thompson, Yiling Lu, Gordon B Mills, Milton Finegold, John A Goss, D Williams Parsons, Sanjeev A Vasudevan, Pavel Sumazin, Dolores López-Terrada, Karl-Dimiter Bissig
BACKGROUND & AIMS: Pediatric liver cancer is a rare but serious disease whose incidence is rising, and for which the therapeutic options are limited. Development of more targeted, less toxic therapies is hindered by the lack of an experimental animal model that captures the heterogeneity and metastatic capability of these tumors. METHODS: Here we established an orthotopic engraftment technique to model a series of patient-derived tumor xenograft (PDTX) from pediatric liver cancers of all major histologic subtypes: hepatoblastoma, hepatocellular cancer and hepatocellular malignant neoplasm...
August 2016: Journal of Hepatology
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
Yael Babichev, Leah Kabaroff, Alessandro Datti, David Uehling, Methvin Isaac, Rima Al-Awar, Michael Prakesch, Ren X Sun, Paul C Boutros, Rosemarie Venier, Brendan C Dickson, Rebecca A Gladdy
BACKGROUND: Leiomyosarcoma (LMS) is a common type of soft tissue sarcoma that responds poorly to standard chemotherapy. Thus the goal of this study was to identify novel selective therapies that may be effective in leiomyosarcoma by screening cell lines with a small molecule library comprised of 480 kinase inhibitors to functionally determine which signalling pathways may be critical for LMS growth. METHODS: LMS cell lines were screened with the OICR kinase library and a cell viability assay was used to identify potentially effective compounds...
2016: Journal of Translational Medicine
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