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Filip Janku, Timothy A Yap, Funda Meric-Bernstam
The PI3K-AKT-mTOR pathway is one of the most frequently dysregulated pathways in cancer and, consequently, more than 40 compounds that target key components of this signalling network have been tested in clinical trials involving patients with a range of different cancers. The clinical development of many of these agents, however, has not advanced to late-phase randomized trials, and the antitumour activity of those that have been evaluated in comparative prospective studies has typically been limited, or toxicities were found to be prohibitive...
March 6, 2018: Nature Reviews. Clinical Oncology
Elvira Schmidt, Johanna Lister, Monika Neumann, Witold Wiecek, Shuai Fu, Anne-Lise Vataire, Jelena Sostar, Shengnan Huang, Florence Marteau
BACKGROUND: Cabozantinib has recently been evaluated as a first-line treatment in advanced renal cell carcinoma (aRCC). OBJECTIVE: To indirectly assess efficacy of cabozantinib versus standard-of-care (SoC) comparators in the first-line treatment of aRCC. METHODS: We conducted a systematic literature review (SLR) to identify randomized controlled studies in the first-line setting for aRCC. The outcomes analyzed were overall survival (OS) and progression-free survival (PFS)...
February 28, 2018: Targeted Oncology
Maria Tsoli, Jie Liu, Laura Franshaw, Han Shen, Cecilia Cheng, MoonSun Jung, Swapna Joshi, Anahid Ehteda, Aaminah Khan, Angel Montero-Carcabosso, Pierre J Dilda, Philip Hogg, David S Ziegler
Diffuse Intrinsic Pontine Gliomas (DIPG) are the most devastating of all pediatric brain tumors. They mostly affect young children and, as there are no effective treatments, almost all patients with DIPG will die of their tumor within 12 months of diagnosis. A key feature of this devastating tumor is its intrinsic resistance to all clinically available therapies. It has been shown that glioma development is associated with metabolic reprogramming, redox state disruption and resistance to apoptotic pathways...
January 26, 2018: Oncotarget
Liye He, Jing Tang, Emma I Andersson, Sanna Timonen, Steffen Koschmieder, Krister Wennerberg, Satu Mustjoki, Tero Aittokallio
The molecular pathways that drive cancer progression and treatment resistance are highly redundant and variable between individual patients with the same cancer type. To tackle this complex rewiring of pathway crosstalk, personalized combination treatments targeting multiple cancer growth and survival pathways are required. Here we implemented a computational-experimental drug combination prediction and testing (DCPT) platform for efficient in silico prioritization and ex vivo testing in patient-derived samples to identify customized synergistic combinations for individual cancer patients...
February 26, 2018: Cancer Research
L Lo Muzio, C Arena, G Troiano, A Villa
BACKGROUND: Traditional treatment of malignancies with chemotherapeutic agents is often affected by the damage inflicted on non-cancerous cells. Toxicities of the oral cavity, such as mucositis and stomatitis, are some of the most significant and unavoidable toxicities associated with anti-cancer therapies. For such reason, in the last decades, newer targeted agents have been developed aiming to decrease the rates of side effects on healthy cells. Unfortunately, targeted anti-cancer therapies also showed significant rate of toxicity on healthy tissues...
March 2018: Oral Diseases
Noboru Nakaigawa, Keiichi Kondo, Tomohiro Kaneta, Ukihide Tateishi, Ryogo Minamimoto, Kazuhiro Namura, Daiki Ueno, Kazuki Kobayashi, Takeshi Kishida, Ichiro Ikeda, Hisashi Hasumi, Kazuhide Makiyama, Narihiko Hayashi, Kimito Osaka, Kentaro Muraoka, Koji Izumi, Takashi Kawahara, Jun-Ichi Teranishi, Yasuhide Miyoshi, Yasushi Yumura, Hiroji Uemura, Tomio Inoue, Masahiro Yao
PURPOSE: We investigated prospectively whether18 F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) can predict the overall survival (OS) of patients with advanced renal cell carcinoma (RCC) previously treated by molecular targeted therapies. METHODS: Between 2009 and 2016, 81 patients who had received single molecular targeted therapies (43 sorafenib, 27 sunitinib, 8 temsirolimus and others) and were scheduled for second line molecular targeted therapies for advanced RCC were enrolled in this prospective study...
February 20, 2018: Cancer Chemotherapy and Pharmacology
Alejandro José Sastre-Heres, Irene Iglesias, Miguel Alaguero-Calero, Daniel Ruiz-Sánchez, Benito García-Díaz, Jaime Peña-Díaz
The aim of this study was to compare the Memorial Sloan-Kettering Cancer Center (MSKCC) and the Cleveland Clinic Foundation (CCF) models of classification of aRCC patients. In addition, the model developed from the pivotal trial of temsirolimus and those proposed by Motzer et al. in 2004, Escudier et al., Heng et al., Choueiri et al. and Bamias et al. were examined. An observational, retrospective study of patients starting first-line systemic therapy was conducted between 2008 and 2011. The variables used to evaluate the classification models were median overall survival (mOS) and median progression-free survival (mPFS)...
February 17, 2018: Pathology Oncology Research: POR
Marina Pulido, Guilhem Roubaud, Anne-Laure Cazeau, Hakim Mahammedi, Lionel Vedrine, Florence Joly, Loic Mourey, Christian Pfister, Alejandro Goberna, Barbara Lortal, Carine Bellera, Philippe Pourquier, Nadine Houédé
BACKGROUND: Bladder cancer is the 7th cause of death from cancer in men and 10th in women. Metastatic patients have a poor prognosis with a median overall survival of 14 months. Until recently, vinflunine was the only second-line chemotherapy available for patients who relapse. Deregulation of the PI3K/AKT/mTOR pathway was observed in more than 40% of bladder tumors and suggested the use of mTOR as a target for the treatment of urothelial cancers. METHODS: This trial assessed the efficacy of temsirolimus in a homogenous cohort of patients with recurrent or metastatic bladder cancer following first-line chemotherapy...
February 17, 2018: BMC Cancer
Maxim Sorokin, Roman Kholodenko, Anna Grekhova, Maria Suntsova, Margarita Pustovalova, Natalia Vorobyeva, Irina Kholodenko, Galina Malakhova, Andrew Garazha, Artem Nedoluzhko, Raif Vasilov, Elena Poddubskaya, Olga Kovalchuk, Leila Adamyan, Vladimir Prassolov, Daria Allina, Denis Kuzmin, Kirill Ignatev, Andreyan Osipov, Anton Buzdin
Acquired resistance to chemotherapy and radiation therapy is one of the major obstacles decreasing efficiency of treatment of the oncologic diseases. In this study, on the two cell lines (ovarian carcinoma SKOV-3 and neuroblastoma NGP-127), we modeled acquired resistance to five target anticancer drugs. The cells were grown on gradually increasing concentrations of the clinically relevant tyrosine kinase inhibitors (TKIs) Sorafenib, Pazopanib and Sunitinib, and rapalogs Everolimus and Temsirolimus, for 20 weeks...
January 12, 2018: Oncotarget
Cuong C Dang, Antonio Peón, Pedro J Ballester
BACKGROUND: Oncology drugs are only effective in a small proportion of cancer patients. Our current ability to identify these responsive patients before treatment is still poor in most cases. Thus, there is a pressing need to discover response markers for marketed and research oncology drugs. Screening these drugs against a large panel of cancer cell lines has led to the discovery of new genomic markers of in vitro drug response. However, while the identification of such markers among thousands of candidate drug-gene associations in the data is error-prone, an appraisal of the effectiveness of such detection task is currently lacking...
February 6, 2018: BMC Medical Genomics
Yuki Iijima, Namiko Fujioka, Yoshinori Uchida, Yoichi Kobayashi, Toshiharu Tsutsui, Yumiko Kakizaki, Yoshihiro Miyashita
A 67-year old man visited our hospital with complaints of fever and cough. He had a past medical history of renal cell carcinoma and had just started treatment with temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor. A 1-week course of antibiotics did not have any effect on his symptoms. Chest computed tomography (CT) scan showed reversed halo sign (RHS). Organizing pneumonia induced by mTOR inhibitor treatment was initially considered. However, transbronchial biopsy revealed clusters of fungal organisms, suggesting infection with Aspergillus spp...
February 3, 2018: International Journal of Infectious Diseases: IJID
D J Inwards, P A Fishkin, B R LaPlant, M T Drake, P J Kurtin, D A Nikcevich, D B Wender, B S Lair, T E Witzig
No abstract text is available yet for this article.
January 29, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Fusao Komada
The aim of this study was to investigate the time-to-onset of drug-induced interstitial lung disease (DILD) following the administration of small molecule molecularly-targeted drugs via the use of the spontaneous adverse reaction reporting system of the Japanese Adverse Drug Event Report database. DILD datasets for afatinib, alectinib, bortezomib, crizotinib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, sorafenib, sunitinib, temsirolimus, and tofacitinib were used to calculate the median onset times of DILD and the Weibull distribution parameters, and to perform the hierarchical cluster analysis...
2018: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Hiroki Kusumoto, Yoshihiko Hirohashi, Satoshi Nishizawa, Masamichi Yamashita, Kazuyo Yasuda, Aiko Murai, Akari Takaya, Takashi Mori, Terufumi Kubo, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Toru Kondo, Noriyuki Sato, Isao Hara, Toshihiko Torigoe
In a previous study, we found that DNAJB8, a heat shock protein (HSP) 40 family member is expressed in kidney cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) and that it has a role in the maintenance of kidney CSCs/CICs. Heat shock factor (HSF) 1 is a key transcription factor for responses to stress including heat shock, and it induces HSP family expression through activation by phosphorylation. In this study, we therefore examined whether heat shock (HS) induces CSCs/CICs. We treated the human kidney cancer cell line ACHN with HS, and found that HS increased side population (SP) cells...
January 8, 2018: Cancer Science
David Schiff, Kurt A Jaeckle, S Keith Anderson, Evanthia Galanis, Caterina Giannini, Jan C Buckner, Phillip Stella, Patrick J Flynn, Bradley J Erickson, John F Schwerkoske, Vesna Kaluza, Erin Twohy, Janet Dancey, John Wright, Jann N Sarkaria
BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible...
January 3, 2018: Cancer
L A Dunn, M G Fury, H Xiao, S S Baxi, E J Sherman, S Korte, C Pfister, S Haque, N Katabi, A L Ho, D G Pfister
No abstract text is available yet for this article.
January 2, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Eva Juengel, Ramin Najafi, Jochen Rutz, Sebastian Maxeiner, Jasmina Makarevic, Frederik Roos, Igor Tsaur, Axel Haferkamp, Roman A Blaheta
Introduction: Although the mechanistic target of rapamycin (mTOR) might be a promising molecular target to treat advanced bladder cancer, resistance develops under chronic exposure to an mTOR inhibitor (everolimus, temsirolimus). Based on earlier studies, we proposed that histone deacetylase (HDAC) blockade might circumvent resistance and investigated whether HDAC inhibition has an impact on growth of bladder cancer cells with acquired resistance towards temsirolimus. Results: The HDAC inhibitor valproic acid (VPA) significantly inhibited growth, proliferation and caused G0/G1 phase arrest in RT112res and UMUC-3res...
December 15, 2017: Oncotarget
Kosuke Mizutani, Kengo Horie, Shingo Nagai, Tomohiro Tsuchiya, Chiemi Saigo, Kazuhiro Kobayashi, Tatsuhiko Miyazaki, Takashi Deguchi
The authors present a case report of collecting duct carcinoma (CDC) that responded to nivolumab, a programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, following the failure of systemic treatment with chemotherapy and targeted therapy. The patient underwent right radical nephrectomy and segmentectomy of the lung following chemotherapy. Fifteen months following the first surgery, segmentectomy and subsequent second-line chemotherapy were performed for recurrence in the lung. Targeted therapy with temsirolimus for recurrence of the lung and lymph node metastases was ultimately used for 30 months...
December 2017: Molecular and Clinical Oncology
Stefan Naulaerts, Cuong C Dang, Pedro J Ballester
Cancer drug therapies are only effective in a small proportion of patients. To make things worse, our ability to identify these responsive patients before administering a treatment is generally very limited. The recent arrival of large-scale pharmacogenomic data sets, which measure the sensitivity of molecularly profiled cancer cell lines to a panel of drugs, has boosted research on the discovery of drug sensitivity markers. However, no systematic comparison of widely-used single-gene markers with multi-gene machine-learning markers exploiting genomic data has been so far conducted...
November 14, 2017: Oncotarget
Tendo Satoh, Takuya Koie, Hirotaka Horiguchi, Noriko Tokui, Satoshi Narita, Chikara Ohyama
Temsirolimus did not demonstrate an efficacy advantage compared with sorafenib as second-line therapy in patients with metastatic renal cell carcinoma (mRCC). Only a few patients achieved complete responses, and the median progression-free survival rate remains short. We report one patient with mRCC who had a continuing response to temsirolimus.
December 2017: Clinical Case Reports
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