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Tumor resistence

Wing-Hin Lee, Ching-Yee Loo, Chean-Ring Leong, Paul M Young, Daniela Traini, Ramin Rohanizadeh
The effectiveness of conventional cancer chemotherapy is hampered by the occurrence of multidrug resistance (MDR) in tumor cells. Although many studies have reported the development of novel MDR chemotherapeutic agents, clinical success is lacking owing to the high associated toxicity. Nanoparticle-based delivery of chemotherapeutic drugs has emerged as alternative approach to treat MDR cancers via exploitation of leaky vasculature in the tumor microenvironment. Accordingly, functionalization of nanoparticles with target specific ligands can be employed to achieve significant improvements in the treatment of MDR cancer...
October 19, 2016: Expert Opinion on Drug Delivery
Hideharu Kimura, Shingo Nishikawa, Hayato Koba, Taro Yoneda, Takashi Sone, Kazuo Kasahara
Epidermal growth factor receptor (EGFR) T790M mutation is associated with resistance to EGFR tyrosine kinase inhibitors' (EGFR-TKIs) in non-small cell lung cancer (NSCLC). The aims of this study are to develop a blood-based, non-invasive approach to detecting the EGFR T790M mutation in advanced NSCLC patients, using PointMan™ EGFR DNA Enrichment Kit which is a novel method for selective amplification of genotype specific sequences.Pairs of blood samples and tumor tissues were collected from NSCLC patients with an EGFR activating mutation and who were resistant to EGFR-TKI treatment...
2016: Advances in Experimental Medicine and Biology
Zhongyan Hua, Xiao Gu, Yudi Dong, Fei Tan, Zhihui Liu, Carol J Thiele, Zhijie Li
Brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB have been reported to be associated with poor prognosis in neuroblastoma (NB) patients. Our previous studies indicated that BDNF activation of TrkB induces chemo-resistance through activation of phosphoinositide-3-kinase (PI3K)/Akt pathway. In this study, we investigated the role of BDNF/TrkB on metastasis in NB. A tetracycline-regulated TrkB-expressing NB cell line (TB3) was used. Scratch wound healing assay, Boyden chamber migration, and invasion assays were performed to study the migration and invasion of TB3 cells...
October 17, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Ashley M Stokes, Charles P Hart, C Chad Quarles
High-grade gliomas are often characterized by hypoxia, which is associated with both poor long-term prognosis and therapy resistance. The adverse role hypoxia plays in treatment resistance and disease progression has led to the development of hypoxia imaging methods and hypoxia-targeted treatments. Here, we determined the tumor hypoxia and vascular perfusion characteristics of 2 rat orthotopic glioma models using 18-fluoromisonidozole positron emission tomography. In addition, we determined tumor response to the hypoxia-activated prodrug evofosfamide (TH-302) in these rat glioma models...
September 2016: Tomography: a Journal for Imaging Research
Y-Q Li, Zw-C Cheng, Sk-W Liu, I Aubert, C S Wong
Inhibition of hippocampal neurogenesis is implicated in neurocognitive dysfunction after cranial irradiation for brain tumors. How irradiation results in impaired neuronal development remains poorly understood. The Trp53 (p53) gene is known to regulate cellular DNA damage response after irradiation. Whether it has a role in disruption of late neuronal development remains unknown. Here we characterized the effects of p53 on neuronal development in adult mouse hippocampus after irradiation. Different bromodeoxyuridine incorporation paradigms and a transplantation study were used for cell fate mapping...
2016: Cell Death Discovery
Minghui Chen, Xueshi Wang, Daolong Zha, Fangfang Cai, Wenjing Zhang, Yan He, Qilai Huang, Hongqin Zhuang, Zi-Chun Hua
Apigenin (APG) is an edible plant-derived flavonoid that shows modest antitumor activities in vitro and in vivo. APG treatment results in cell growth arrest and apoptosis in various types of tumors by modulating several signaling pathways. In the present study, we evaluated interactions between APG and TRAIL in non-small cell lung cancer (NSCLC) cells. We observed a synergistic effect between APG and TRAIL on apoptosis of NSCLC cells. A549 cells and H1299 cells were resistant to TRAIL treatment alone. The presence of APG sensitized NSCLC cells to TRAIL-induced apoptosis by upregulating the levels of death receptor 4 (DR4) and death receptor 5 (DR5) in a p53-dependent manner...
October 18, 2016: Scientific Reports
Maximilian Boesch, Sieghart Sopper, Alain G Zeimet, Daniel Reimer, Guenther Gastl, Burkhard Ludewig, Dominik Wolf
Malignancy is fuelled by distinct subsets of stem-like cells which persist under treatment and provoke drug-resistant recurrence. Eradication of these cancer stem cells has therefore become a prime objective for the development and design of novel classes of anti-cancer therapeutics with improved clinical efficacy. Here, we portray potentially clinically-relevant hallmarks of cancer stem cells and focus on their recently appreciated properties of cell variability and plasticity, both of which make them elusive targets for cancer therapies...
October 15, 2016: Biochimica et Biophysica Acta
Lezi Chen, Quan Chen, Guosan Deng, Wenbin Xie, Jihong Lian, Mian Wang, Huilan Zhu
Recent studies suggest that forced activation of AMP-activated protein kinase (AMPK) could inhibit melanoma cell proliferation. In this report, we evaluated the anti-melanoma cell activity by a novel small-molecular AMPK activator, GSK621. Treatment of GSK621 decreased survival and proliferation of human melanoma cells (A375, WM-115 and SK-Mel-2 lines), which was accompanied by activation of caspase-3/-9 and apoptosis. Reversely, caspase inhibitors attenuated GSK621-induced cytotoxicity against melanoma cells...
October 14, 2016: Biochemical and Biophysical Research Communications
Glenwood Goss, Chun-Ming Tsai, Frances A Shepherd, Lyudmila Bazhenova, Jong Seok Lee, Gee-Chen Chang, Lucio Crino, Miyako Satouchi, Quincy Chu, Toyoaki Hida, Ji-Youn Han, Oscar Juan, Frank Dunphy, Makoto Nishio, Jin-Hyoung Kang, Margarita Majem, Helen Mann, Mireille Cantarini, Serban Ghiorghiu, Tetsuya Mitsudomi
BACKGROUND: Osimertinib (AZD9291) is an oral, potent, irreversible EGFR tyrosine-kinase inhibitor selective for EGFR tyrosine-kinase inhibitor sensitising mutations, and the EGFR Thr790Met resistance mutation. We assessed the efficacy and safety of osimertinib in patients with EGFR Thr790Met-positive non-small-cell lung cancer (NSCLC), who had progressed after previous therapy with an approved EGFR tyrosine-kinase inhibitor. METHODS: In this phase 2, open-label, single-arm study (AURA2), patients aged at least 18 years with centrally confirmed EGFR Thr790Met-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC who progressed on previous EGFR tyrosine-kinase inhibitor therapy received osimertinib 80 mg orally once daily; treatment could continue beyond progression if the investigator observed a clinical benefit...
October 14, 2016: Lancet Oncology
Juan Bai, Ying Zhu, Ying Dong
ETHNOPHARMACOLOGICAL RELEVANCE: Bitter melon (Momordica charantia L.) is rich in a variety of biologically active ingredients, and has been widely used in traditional Chinese medicine (TCM) to treat various diseases, including type 2 diabetes and obesity. AIM OF THE STUDY: We aimed to investigate how bitter melon powder (BMP) could affect obesity-associated inflammatory responses to ameliorate high-fat diet (HFD)-induced insulin resistance, and investigated whether its anti-inflammatory properties were effected by modulating the gut microbiota...
October 14, 2016: Journal of Ethnopharmacology
Alice Iezzi, Elisa Caiola, Massimo Broggini
The Phosphatidyl inositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and c-Met signaling pathways are often deregulated in cancer. The two pathways are interconnected and at least c-Met has been implicated in drug resistance. The aim of the study was to assess in ovarian cancer preclinical models, the efficacy and tolerability of a dual PI3K mTOR inhibitor (PF-05212384 or gedatolisib) and a c-Met inhibitor (crizotinib) either as single agents or in combination. In vitro, both PF-05212384 and crizotinib showed a concentration dependent activity in the two ovarian cancer cell lines...
October 2016: Translational Oncology
Bishoy M Faltas, Davide Prandi, Scott T Tagawa, Ana M Molina, David M Nanus, Cora Sternberg, Jonathan Rosenberg, Juan Miguel Mosquera, Brian Robinson, Olivier Elemento, Andrea Sboner, Himisha Beltran, Francesca Demichelis, Mark A Rubin
Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime...
October 17, 2016: Nature Genetics
Axel Bode, Kambiz Rahbar, Julia Konnert, Martin Bögemann, Lars Stegger
A 66-year-old man with castration-resistant prostate carcinoma and multiple symptomatic bone mestastases was considered for Ra-dichloride (Xofigo) therapy. Staging with Ga-PSMA-PET/CT revealed additional extensive tumor involvement of the spine without relevant uptake in bone scintigraphy. Based on this imaging result, the patient was rescheduled for a PSMA-targeted therapy. Additional Ga-PSMA-PET/CT may have a considerable benefit for patients considered for Xofigo.
October 5, 2016: Clinical Nuclear Medicine
Daniel H Hovelson, Scott A Tomlins
Molecular biomarkers play little role in the current treatment of metastatic castration-resistant prostate cancer (CRPC). The advent of next-generation sequencing (NGS) has enabled the comprehensive molecular characterization of the genomic and transcriptomic landscape of both untreated primary prostate cancer and CRPC. Recent studies demonstrating the feasibility of interinstitution studies obtaining and NGS profiling of metastatic biopsies, targeted NGS approaches applicable to routine formalin-fixed, paraffin-embedded specimens, and NGS approaches applicable to circulating DNA and circulating tumor cells portend near-term adoption of NGS approaches in the management and treatment of CRPC...
September 2016: Cancer Journal
Elena Castro, Joaquin Mateo, David Olmos, Johann S de Bono
Several genomic studies have identified DNA repair gene defects in prostate cancer in the last 5 years. The mechanisms by which these DNA repair defects promote carcinogenesis and tumor progression in the prostate have not been fully elucidated, but their presence in at least 20-25% of metastatic castration-resistant prostate cancers (CRPCs) provides an opportunity for a therapeutic strategy that turns a tumor strength into its weakness and may lead to arguably the first molecularly stratified treatment for this disease...
September 2016: Cancer Journal
Oliver Sartor
Radiopharmaceuticals used in the treatment of castrate-resistant prostate cancer are reviewed herein with an emphasis on sequential and combination therapies. Four bone-seeking radiopharmaceuticals had been approved in the United States. Three of these are β-emitters (phosphorus-32, strontium-89, samarium-153-ethylenediaminetetramethylene-phosphonic acid) that are approved for palliative purposes. One α-emitter (radium-223 [Ra]) is approved for prolongation of survival in bone metastatic castrate-resistant prostate cancer...
September 2016: Cancer Journal
Zachery R Reichert, Maha Hussain
The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen deprivation therapy. This foundation of treatment has a high rate of biochemical and clinical response and meaningful clinical benefit but is finite in duration as most cancers will progress to castration resistance. Historically, treatment for mCRPC entailed androgen receptor (AR) inhibitors (nilutamide, flutamide, bicalutamide), nonspecific steroidal biosynthesis inhibitors (ketoconazole, itraconazole), steroids (prednisone, diethylstilbesterol, dexamethasone), or palliative chemotherapy (mitoxantrone, estramustine), but none of these strategies impacted survival...
September 2016: Cancer Journal
Daniel C Danila, Aliaksandra Samoila, Chintan Patel, Nicole Schreiber, Amrita Herkal, Aseem Anand, Diogo Bastos, Glenn Heller, Martin Fleisher, Howard I Scher
Circulating tumor cell (CTC) number measured with the CellSearch assay is prognostic for survival in metastatic castration-resistant prostate cancer before and after therapy. Using a standard operating protocol for sample collection, processing, and analysis, we compared detection rates of CellSearch performed using US Food and Drug Administration-cleared methodology with a second positive selection assay, AdnaTest, and a nonselection polymerase chain reaction (PCR)-based (direct detection PCR [DDPCR]) assay in 55 blood samples from 47 men with progressive metastatic castration-resistant prostate cancer...
September 2016: Cancer Journal
Ana Kober Nogueira Leite, Marco Aurélio Vamondes Kulcsar, Beatriz de Godoi Cavalheiro, Evandro Sobroza de Mello, Venâncio Avancini F Alves, Claudio Roberto Cernea, Leandro Luongo Matos
OBJECTIVE: The purpose of the present study was to investigate the predictive factors for worse disease-specific survival in patients with pulmonary disease secondary to differentiated thyroid cancer. METHODS: This was a retrospective cohort study conducted over a 5-year period that included 54 patients with pulmonary disease secondary to DTC during the follow-up. Among these patients, 13 (24.1%) died from the disease. Dedifferentiation characteristics were identified at pathological examination of the metastatic disease (lymph node or distant metastases), and was defined as the abrupt transformation of a well-differentiated tumor into high grade morphology that lacks the original distinct histologic characteristics...
October 17, 2016: Endocrine Practice
Hong Jiang, Dongming Geng, Hongqia Liu, Zhengrong Li, Jing Cao
CONTEXT: Gastric carcinoma (GC) is one of the most common cancers and the second most frequent cause of cancer-related deaths. Chemotherapy is an important therapeutic modality for GC. However, chemoresistance limited its success rate. Combination chemotherapy is often applied to prevent drug-induced resistance in cancers. OBJECTIVE: The aim of this study is to evaluate whether the co-delivery of etoposide (ETP) and curcumin (CUR) with one nanoparticle can result in synergistic effects of both drugs...
October 17, 2016: Drug Delivery
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