Read by QxMD icon Read


Aleksandra Divac Rankov, Mila Ljujić, Marija Petrić, Dragica Radojković, Milica Pešić, Jelena Dinić
Autophagy is linked to multiple cancer-related signaling pathways, and represents a defense mechanism for cancer cells under therapeutic stress. The crosstalk between apoptosis and autophagy is essential for both tumorigenesis and embryonic development. We studied the influence of autophagy on cell survival in pro-apoptotic conditions induced by anticancer drugs in three model systems: human cancer cells (NCI-H460, COR-L23 and U87), human normal cells (HaCaT and MRC-5) and zebrafish embryos (Danio rerio). Autophagy induction with AZD2014 and tamoxifen antagonized the pro-apoptotic effect of chemotherapeutics doxorubicin and cisplatin in cell lines, while autophagy inhibition by wortmannin and chloroquine synergized the action of both anticancer agents...
June 29, 2017: Histochemistry and Cell Biology
S T Kim, S Y Kim, S J Klempner, J Yoon, N Kim, S Ahn, H Bang, K-M Kim, W Park, S H Park, J O Park, Y S Park, H Y Lim, S H Lee, K Park, W K Kang, J Lee
Background: Targeting oncogenic genomic aberrations is an established therapeutic strategy in multiple tumor types. Molecular classification has uncovered a number of novel targets, and rapamycin-insensitive companion of mTOR (RICTOR) amplification has been identified in lung cancer. Further investigation assessing the therapeutic potential of RICTOR amplification as a novel target across advanced cancers is needed. Patients and methods: Tumor samples from 640 patients with metastatic solid tumors, primarily gastrointestinal and lung cancers were prospectively subjected to a next-generation sequencing (NGS) assay to identify molecular targets...
March 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Nneha Sakre, Gary Wildey, Mohadese Behtaj, Adam Kresak, Michael Yang, Pingfu Fu, Afshin Dowlati
Small cell lung cancer (SCLC) is an aggressive cancer that represents ~15% of all lung cancers. Currently there are no targeted therapies to treat SCLC. Our genomic analysis of a metastatic SCLC cohort identified recurrent RICTOR amplification. Here, we examine the translational potential of this observation. RICTOR was the most frequently amplified gene observed (~14% patients), and co-amplified with FGF10 and IL7R on chromosome 5p13. RICTOR copy number variation correlated with RICTOR protein expression in SCLC cells...
January 24, 2017: Oncotarget
Sophie Broutin, Adam Stewart, Parames Thavasu, Angelo Paci, Jean-Michel Bidart, Udai Banerji
BACKGROUND: We aimed to understand the dependence of MEK and m-TOR inhibition in EGFR(WT)/ALK(non-rearranged) NSCLC cell lines. METHODS: In a panel of KRAS(M) and KRAS(WT) NSCLC cell lines, we determined growth inhibition (GI) following maximal reduction in p-ERK and p-S6RP caused by trametinib (MEK inhibitor) and AZD2014 (m-TOR inhibitor), respectively. RESULTS: GI caused by maximal m-TOR inhibition was significantly greater than GI caused by maximal MEK inhibition in the cell line panel (52% vs 18%, P<10(-4))...
August 23, 2016: British Journal of Cancer
H Zhong, C Fazenbaker, C Chen, S Breen, J Huang, X Yao, P Ren, Y Yao, R Herbst, R E Hollingsworth
Colorectal cancer (CRC) is a heterogeneous disease with a broad spectrum of genetic and epigenetic changes. A comprehensive molecular characterization of CRC by The Cancer Genome Atlas Network detected the overexpression of the insulin-like growth factor 2 (IGF2) gene, encoding a ligand for the insulin-like growth factor 1 receptor (IGF-1R), in a subset of CRC tumors. In this study, we investigated the oncogenic potential of IGF-2 in IGF2-overexpressing CRC models and the efficacy of MEDI-573, an IGF-1/2-neutralizing antibody...
February 9, 2017: Oncogene
Hee Kyung Kim, Sun Young Kim, Su Jin Lee, Mihyeon Kang, Seung Tae Kim, Jiryeon Jang, Oliver Rath, Julia Schueler, Dong Woo Lee, Woong Yang Park, Sung Joo Kim, Se Hoon Park, Jeeyun Lee
BACKGROUND: Although pazopanib treatment has become the standard chemotherapy in salvage setting for metastatic sarcoma patients, most patients progress after pazopanib treatment in 4 to 6 months. After failure to pazopanib, patients have limited options for treatment. Therefore, subsequent therapy in patients who failed to pazopanib is urgently needed and the use of patient derived cells or patient derived tumors for accompanying testing with various pharmacological inhibitors could offer additional treatment options for these patients...
June 2016: Translational Oncology
Chih-Chia Yu, Hsien-bin Huang, Shih-Kai Hung, Hui-Fen Liao, Ching-Chih Lee, Hon-Yi Lin, Szu-Chin Li, Hsu-Chueh Ho, Chung-Lin Hung, Yu-Chieh Su
BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common malignant neoplasms in Taiwan. Activation of the mTOR signaling pathway has been linked to decreased radiation responsiveness in human oral cancer, thus it limits efficacy of radiotherapy. To address this question, we investigated the effect of AZD2014, a novel small molecular ATP-competitive inhibitor of mTORC1 and mTORC2 kinase, as a radiosensitizer in primary OSCC and OSCC-derived cell line models. METHODS: We isolated primary tumor cells from OSCC tissues and cell lines...
2016: PloS One
James T Lynch, Robert McEwen, Claire Crafter, Ultan McDermott, Mathew J Garnett, Simon T Barry, Barry R Davies
Selective phosphoinositide 3-kinase (PI3K)/AKT/mTOR inhibitors are currently under evaluation in clinical studies. To identify tumor types that are sensitive to PI3K pathway inhibitors we screened compounds targeting PI3Kα/δ (AZD8835), PI3Kβ/δ (AZD8186), AKT (AZD5363) and mTORC1/2 (AZD2014) against a cancer cell line panel (971 cell lines). There was an enrichment of hematological malignancies that were sensitive to AKT and mTOR inhibition, with the greatest degree of sensitivity observed in T-cell acute lymphoblastic leukemia (T-ALL)...
April 19, 2016: Oncotarget
Timon Vandamme, Matthias Beyens, Ken Op de Beeck, Fadime Dogan, Peter M van Koetsveld, Patrick Pauwels, Geert Mortier, Christel Vangestel, Wouter de Herder, Guy Van Camp, Marc Peeters, Leo J Hofland
BACKGROUND: The mTOR-inhibitor everolimus improves progression-free survival in advanced pancreatic neuroendocrine tumours (PNETs). However, adaptive resistance to mTOR inhibition is described. METHODS: QGP-1 and BON-1, two human PNET cell lines, were cultured with increasing concentrations of everolimus up to 22 weeks to reach a dose of 1 μM everolimus, respectively, 1000-fold and 250-fold initial IC50. Using total DNA content as a measure of cell number, growth inhibitory dose-response curves of everolimus were determined at the end of resistance induction and over time after everolimus withdrawal...
March 15, 2016: British Journal of Cancer
Masako Harada, Juliana Benito, Shinichi Yamamoto, Surinder Kaur, Dirim Arslan, Santiago Ramirez, Rodrigo Jacamo, Leonidas Platanias, Hiromichi Matsushita, Tsutomu Fujimura, Saiko Kazuno, Kensuke Kojima, Yoko Tabe, Marina Konopleva
Mammalian target of rapamycin (mTOR) signaling is a critical pathway in the biology of acute myeloid leukemia (AML). Proviral integration site for moloney murine leukemia virus (PIM) serine/threonine kinase signaling takes part in various pathways exerting tumorigenic properties. We hypothesized that the combination of a PIM kinase inhibitor with an mTOR inhibitor might have complementary growth-inhibitory effects against AML. The simultaneous inhibition of the PIM kinase by pan-PIM inhibitor AZD1208 and of mTOR by selective mTORC1/2 dual inhibitor AZD2014 exerted anticancer properties in AML cell lines and in cells derived from primary AML samples with or without supportive stromal cell co-culture, leading to suppressed proliferation and increased apoptosis...
November 10, 2015: Oncotarget
Thomas Powles, Matthew Wheater, Omar Din, Thomas Geldart, Ekaterini Boleti, Andrew Stockdale, Santhanam Sundar, Angus Robinson, Imtiaz Ahmed, Akhila Wimalasingham, Wendy Burke, Shah-Jalal Sarker, Syed Hussain, Christy Ralph
BACKGROUND: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2). OBJECTIVE: The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC...
March 2016: European Urology
Katherine R Singleton, Trista K Hinz, Emily K Kleczko, Lindsay A Marek, Jeff Kwak, Taylor Harp, Jihye Kim, Aik Choon Tan, Lynn E Heasley
The FGFR1 is a therapeutic target under investigation in multiple solid tumors and clinical trials of selective tyrosine kinase inhibitors (TKI) are underway. Treatment with a single TKI represents a logical step toward personalized cancer therapy, but intrinsic and acquired resistance mechanisms limit their long-term benefit. In this study, we deployed RNAi-based functional genomic screens to identify protein kinases controlling the intrinsic sensitivity of FGFR1-dependent lung cancer and head and neck squamous cell cancer (HNSCC) cells to ponatinib, a multikinase FGFR-active inhibitor...
October 15, 2015: Cancer Research
Sylvie M Guichard, Jon Curwen, Teeru Bihani, Celina M D'Cruz, James W T Yates, Michael Grondine, Zoe Howard, Barry R Davies, Graham Bigley, Teresa Klinowska, Kurt G Pike, Martin Pass, Christine M Chresta, Urszula M Polanska, Robert McEwen, Oona Delpuech, Stephen Green, Sabina C Cosulich
mTOR is an atypical serine threonine kinase involved in regulating major cellular functions, such as nutrients sensing, growth, and proliferation. mTOR is part of the multiprotein complexes mTORC1 and mTORC2, which have been shown to play critical yet functionally distinct roles in the regulation of cellular processes. Current clinical mTOR inhibitors only inhibit the mTORC1 complex and are derivatives of the macrolide rapamycin (rapalogs). Encouraging effects have been observed with rapalogs in estrogen receptor-positive (ER(+)) breast cancer patients in combination with endocrine therapy, such as aromatase inhibitors...
November 2015: Molecular Cancer Therapeutics
Roberta L Beauchamp, Marianne F James, Patrick A DeSouza, Vilas Wagh, Wen-Ning Zhao, Justin T Jordan, Anat Stemmer-Rachamimov, Scott R Plotkin, James F Gusella, Stephen J Haggarty, Vijaya Ramesh
Meningiomas are the most common primary intracranial adult tumor. All Neurofibromatosis 2 (NF2)-associated meningiomas and ~60% of sporadic meningiomas show loss of NF2 tumor suppressor protein. There are no effective medical therapies for progressive and recurrent meningiomas. Our previous work demonstrated aberrant activation of mTORC1 signaling that led to ongoing clinical trials with rapamycin analogs for NF2 and sporadic meningioma patients. Here we performed a high-throughput kinome screen to identify kinases responsible for mTORC1 pathway activation in NF2-deficient meningioma cells...
July 10, 2015: Oncotarget
Euphemia Y Leung, Marjan Askarian-Amiri, Graeme J Finlay, Gordon W Rewcastle, Bruce C Baguley
The mammalian target of rapamycin (mTOR), a vital component of signaling pathways involving PI3K/AKT, is an attractive therapeutic target in breast cancer. Everolimus, an allosteric mTOR inhibitor that inhibits the mTOR functional complex mTORC1, is approved for treatment of estrogen receptor positive (ER+) breast cancer. Other mTOR inhibitors show interesting differences in target specificities: BEZ235 and GSK2126458 are ATP competitive mTOR inhibitors targeting both PI3K and mTORC1/2; AZD8055, AZD2014 and KU-0063794 are ATP competitive mTOR inhibitors targeting both mTORC1 and mTORC2; and GDC-0941 is a pan-PI3K inhibitor...
2015: PloS One
Bristi Basu, Emma Dean, Martina Puglisi, Alastair Greystoke, Michael Ong, Wendy Burke, Maria Cavallin, Graham Bigley, Christopher Womack, Elizabeth A Harrington, Stephen Green, Elisabeth Oelmann, Johann S de Bono, Malcolm Ranson, Udai Banerji
PURPOSE: AZD2014 is a novel, oral, m-TORC 1/2 inhibitor that has shown in vitro and in vivo efficacy across a range of preclinical human cancer models. EXPERIMENTAL DESIGN: A rolling six-dose escalation was performed to define an MTD (part A), and at MTD a further cohort of patients was treated to further characterize toxicities and perform pre- and posttreatment biopsies (part B). AZD2014 was administered orally twice a day continuously. Flow cytometry, ELISA, and immunohistochemistry were used to quantify pharmacodynamic biomarkers...
August 1, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Hui Liao, Yu Huang, Botang Guo, Bo Liang, Xincheng Liu, Huohui Ou, Chenglong Jiang, Xianghong Li, Dinghua Yang
The mammalian target of rapamycin (mTOR) has emerged as a critical effector in cell growth, proliferation, survival, angiogenesis, and autophagy through direct interaction with mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2). The mTOR axis is aberrantly activated in about 50% of human hepatocellular carcinoma (HCC) cases and thus has become an attractive target for drug development in this disease. Allosteric inhibitors of mTORC1, rapamycin and its derivatives have been used to study in patients with HCC but have not shown significant clinical utility, likely because of the lack of inhibition of mTORC2...
2015: American Journal of Cancer Research
Haihong Zhong, Christine Fazenbaker, Shannon Breen, Cui Chen, Jiaqi Huang, Christopher Morehouse, Yihong Yao, Robert E Hollingsworth
MEDI-573 is a human antibody that neutralizes insulin-like growth factor (IGF) I and IGFII. IGFs are overexpressed in multiple types of cancer; their overexpression is a potential mechanism for resistance to IGFI receptor (IGFIR)-targeting therapy. Effects of IGF on cell proliferation, differentiation, and survival are mediated through its binding to and activation of IGFIR or insulin receptor A (IR-A). In this study, we measured the mRNA levels of IGFI, IGFII, and IGFIR in human pediatric sarcoma xenografts, and protein levels in sarcoma cell lines...
November 2014: Molecular Cancer Therapeutics
Daniel Martin, Yi Li, Junyao Yang, Gang Wang, Andriana Margariti, Zhixin Jiang, Hui Yu, Anna Zampetaki, Yanhua Hu, Qingbo Xu, Lingfang Zeng
It is well known that atherosclerosis occurs geographically at branch points where disturbed flow predisposes to the development of plaque via triggering of oxidative stress and inflammatory reactions. In this study, we found that disturbed flow activated anti-oxidative reactions via up-regulating heme oxygenase 1 (HO-1) in an X-box-binding protein 1 (XBP1) and histone deacetylase 3 (HDAC3)-dependent manner. Disturbed flow concomitantly up-regulated the unspliced XBP1 (XBP1u) and HDAC3 in a VEGF receptor and PI3K/Akt-dependent manner...
October 31, 2014: Journal of Biological Chemistry
Scott A Ezell, Michele Mayo, Teeru Bihani, Suprawee Tepsuporn, Suping Wang, Melissa Passino, Shaun E Grosskurth, Mike Collins, Julie Parmentier, Corinne Reimer, Kate F Byth
Diffuse large B cell lymphoma is generally treated by chemotherapy and there is an unmet medical need for novel targeted therapies or combination therapies. Using in vitro screening, we have identified the combination of ibrutinib, an inhibitor of the tyrosine kinase BTK, and AZD2014, an mTOR catalytic inhibitor, as being highly synergistic in killing ABC-subtype DLBCL cell lines. Simultaneous inhibition of BTK and mTOR causes apoptosis both in vitro and in vivo and results in tumor regression in a xenograft model...
July 15, 2014: Oncotarget
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"