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Targeted therapies lung cancer

Qiong Xie, Zipu Yu, Yuan Lu, Jingya Fan, Yiming Ni, Liang Ma
Son of sevenless (SOS) is one of the guanine nucleotide exchange factors that can regulate the mitogen-activated protein kinase/extracellular signal regulated kinase signal pathway via controlling the activation of Ras. microRNAs are key regulon of gene expression and would be treated as tumor biomarkers or therapeutic targets. In this study, we find that miR-148a-3p acts as a tumor-suppressor in the development and progression of non-small-cell lung cancer (NSCLC). miR-148a-3p inhibits NSCLC cells proliferation and epithelial-mesenchymal transition by reducing the expression of SOS2, which refers Ras activating...
December 10, 2018: Journal of Cellular Physiology
A Kobayashi, N Autsavapromporn, T A F Tengku Ahmad, M Oikawa, S Homma-Takeda, Y Furusawa, J Wang, T Konishi
Bi-directional signaling involved in radiation-induced bystander effect (RIBE) between irradiated carcinoma cells and their surrounding non-irradiated normal cells is relevant to radiation cancer therapy. Using the SPICE-NIRS microbeam, we delivered 500 protons to A549-GFP lung carcinoma cells, stably expressing H2B-GFP, which were co-cultured with normal WI-38 cells. The level of γ-H2AX, a marker for DNA double-strand breaks (DSB), was subsequently measured up to 24-h post-irradiation in both targeted and bystander cells...
December 11, 2018: Radiation Protection Dosimetry
Yu Sakurai, Tomoya Hada, Akari Kato, Yuta Hagino, Wataru Mizumura, Hideyoshi Harashima
Although metastatic cancer is a major cause of death for cancer patients, no efficacious treatment for metastasis is available. We previously showed that the growth of a primary tumor could be inhibited by the administration of an anti-angiogenic small interfering RNA (siRNA) that is encapsulated in an RGD peptide-modified lipid nanoparticle (RGD-LNP). We herein report on the delivery of siRNA by an RGD-LNP to the vasculature is also effective for treating metastatic tumors. We compared the RGD-LNP with the polyethylene glycol (PEG)ylated LNP (PEG-LNP) in terms of accumulation in a lung-metastasized model...
December 21, 2018: Molecular Therapy Oncolytics
Hao Liu, Liquan Gao, Xinhe Yu, Lijun Zhong, Jiyun Shi, Bing Jia, Nan Li, Zhaofei Liu, Fan Wang
Integrin αvβ6 is expressed at an undetectable level in normal tissues, but is remarkably upregulated during many pathological processes, especially in cancer and fibrosis. Noninvasive imaging of integrin αvβ6 expression using a radiotracer with favorable in vivo pharmacokinetics would facilitate disease diagnosis and therapy monitoring. Through disulfide-cyclized method, we synthesized in this study, a new integrin αvβ6-targeted cyclic peptide (denoted as cHK), and radiolabeled it with 99m Tc. The ability of the resulting radiotracer 99m Tc-HYNIC-cHK to detect integrin αvβ6 expression in pancreatic cancer xenografts and idiopathic pulmonary fibrosis was evaluated using small-animal single-photon emission computed tomography (SPECT)/computed tomography (CT)...
2018: Biophysics Reports
Jian Liu, Doudou Zhang, Shu Lian, Junxia Zheng, Bifei Li, Tao Li, Lee Jia
Background: Gefitinib (Gef), an important epidermal growth factor receptor (EGFR), is used to treat lung cancer, but low water solubility and poor bioavailability severely limit its application in cancer therapy. Methods: In this study, nanographene oxide (NGO) was decorated with hyaluronic acid (HA) by a linker cystamine dihydrochloride containing disulfide bonds (-SS-), followed by the incorporation of gefitinib, thus, constructing a HA-functionalized GO-based gefitinib delivery system (NGO-SS-HA-Gef)...
2018: International Journal of Nanomedicine
Tatsunori Nishimura, Asuka Nakata, Xiaoxi Chen, Kurumi Nishi, Makiko Meguro-Horike, Soichiro Sasaki, Kenji Kita, Shin-Ichi Horike, Kaori Saitoh, Keiko Kato, Kaori Igarashi, Takahiko Murayama, Susumu Kohno, Chiaki Takahashi, Naofumi Mukaida, Seiji Yano, Tomoyoshi Soga, Arinobu Tojo, Noriko Gotoh
Tumor recurrence is attributable to cancer stem-like cells (CSCs), the metabolic mechanisms of which currently remain obscure. Here, we uncovered the critical role of folate-mediated one-carbon (1C) metabolism involving mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and its downstream purine synthesis pathway. MTHFD2 knockdown greatly reduced tumorigenesis and stem-like properties, which were associated with purine nucleotide deficiency, and caused marked accumulation of 5-aminoimidazole carboxamide ribonucleotide (AICAR)-the final intermediate of the purine synthesis pathway...
December 7, 2018: Oncogene
Nasser K Altorki, Geoffrey J Markowitz, Dingcheng Gao, Jeffrey L Port, Ashish Saxena, Brendon Stiles, Timothy McGraw, Vivek Mittal
Lung cancer is a major global health problem, as it is the leading cause of cancer-related deaths worldwide. Major advances in the identification of key mutational alterations have led to the development of molecularly targeted therapies, whose efficacy has been limited by emergence of resistance mechanisms. US Food and Drug Administration (FDA)-approved therapies targeting angiogenesis and more recently immune checkpoints have reinvigorated enthusiasm in elucidating the prognostic and pathophysiological roles of the tumour microenvironment in lung cancer...
December 10, 2018: Nature Reviews. Cancer
Anna Scattone, Annamaria Catino, Laura Schirosi, Lucia Caldarola, Stefania Tommasi, Rosanna Lacalamita, Elisabetta Sara Montagna, Domenico Galetta, Gabriella Serio, Francesco Alfredo Zito, Anita Mangia
BACKGROUND: Anaplastic lymphoma kinase (ALK) rearrangement represents a landmark in the targeted therapy of non-small cell lung cancer (NSCLC). Immunohistochemistry (IHC) is a sensitive and specific method to detect ALK protein expression, possibly an alternative to fluorescence in situ hybridization (FISH). In this study, the concordance of FISH and IHC to determine ALK status was evaluated, particularly focusing on discordant cases. MATERIALS AND METHODS: ALK status was tested by FISH and the IHC validated method (Ventana ALK (D5F3) CDx Assay) in 95 NSCLCs...
December 4, 2018: Translational Oncology
Carmen Teijeiro-Valiño, Ramon Novoa-Carballal, Erea Borrajo, Anxo Vidal, Marta Alonso-Nocelo, María de la Fuente Freire, Pedro P Lopez-Casas, Manuel Hidalgo, Noémi Csaba, María José Alonso
So far, the success of anticancer nanomedicines has been moderate due to their lack of adequate targeting properties and/or to their difficulties penetrating tumors. Here we report a multifunctional drug nanocarrier consisting of hyaluronic acid nanocapsules conjugated with the tumor homing peptide tLyp1, which exhibits both, dual targeting properties (to the tumor and to the lymphatics), and enhanced tumor penetration. Data from a 3D co-culture in vitro model showed the capacity of these nanocapsules to interact with the NRP1 receptors over-expressed in cancer cells...
December 7, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Yingjie Xu, Jingbo Wang, Zhihui Hu, Yuan Tian, Pan Ma, Shuai Li, Jianrong Dai, Shulian Wang
The present study aimed to compare 4 techniques in the planning of locoregional irradiation including internal mammary nodal region for left-sided breast cancer. Ten patients with left-sided breast cancer undergoing breast conservation surgery were enrolled. For each patient, 4 treatment plans were performed: a helical tomotherapy (HT) plan, a volumetric modulated arc therapy (VMAT) plan, a static intensity modulated radiation therapy (IMRT) plan, and a hybrid IMRT plan, designed to encompass the whole breast, internal mammary, and supraclavicular nodal regions...
October 24, 2018: Medical Dosimetry: Official Journal of the American Association of Medical Dosimetrists
Julie Kang, Jun Young Lee, İsa Taş, Kunal N More, Hangun Kim, Jeong-Hoon Park, Dong-Jo Chang
Heat-shock protein 90 (HSP90) is a molecular chaperone that activates oncogenic transformation in several solid tumors, including lung and breast cancers. Ganetespib, a most promising candidate among several HSP90 inhibitors under clinical trials, has entered Phase III clinical trials for cancer therapy. Despite numerous evidences validating HSP90 as a target of anticancer, there are few studies on PET agents targeting oncogenic HSP90. In this study, we synthesized and biologically evaluated a novel 18 F-labeled 5-resorcinolic triazolone derivative (1, [18 F]PTP-Ganetespib) based on ganetespib...
October 23, 2018: Bioorganic & Medicinal Chemistry Letters
Bei Cheng, Feng Gao, Erica Maissy, Peisheng Xu
Suramin (SM), a drug for African sleeping sickness and river blindness therapy, has been investigated in various clinical trials for cancer therapy. However, SM was eventually withdrawn from the market because of its narrow therapeutic window and the side effects associated with multiple targets. In this work, we developed a simple but effective system based on a nontoxic dose of SM combined with a chemotherapeutic agent for the treatment of metastatic triple-negative breast cancer (TNBC). SM and glycol chitosan (GCS) formed nanogels because of the electrostatic effect, whereas doxorubicin (DOX) was incorporated into the system through the hydrophilic and hydrophobic interactions between DOX and GCS as well as the ionic interactions between DOX and SM to yield GCS-SM/DOX nanoparticles (NPs)...
December 5, 2018: Acta Biomaterialia
James Rijken, Tanya Kairn, Scott Crowe, Jamie Trapp
Due to large doses per fraction, stereotactic ablative radiotherapy of lung or spine can lead to skin tissue toxicity, the amount of which depends on a variety of factors such as target location, beam geometry, and immobilization. The effect of arc length on spreading out entrance and exit doses and the corresponding predictions of skin reactions has not yet been studied for stereotactic body radiotherapy volumetric modulated arc therapy (VMAT) treatments. 58 clinically relevant VMAT stereotactic body radiotherapy spine and lung plans were created for an anthropomorphic phantom utilizing a range of target locations, beam geometries and arc lengths...
December 4, 2018: Medical Dosimetry: Official Journal of the American Association of Medical Dosimetrists
Florencia Rago, Matthew T DiMare, GiNell Elliott, David A Ruddy, Sosathya Sovath, Grainne Kerr, Hyo-Eun C Bhang, Zainab Jagani
Recent studies have highlighted that cancer cells with a loss of the SWI/SNF complex catalytic subunit BRG1 are dependent on the remaining ATPase, BRM, making it an attractive target for cancer therapy. However, an understanding of the extent of target inhibition required to arrest cell growth, necessary to develop an appropriate therapeutic strategy, remains unknown. Here, we utilize tunable depletion of endogenous BRM using the SMASh degron, and interestingly observe that BRG1-mutant lung cancer cells require near complete depletion of BRM to robustly inhibit growth both in vitro and in vivo...
November 20, 2018: Biochemical and Biophysical Research Communications
Xiaofen Li, Qingtian Huang, Huidan Long, Peiquan Zhang, Huabo Su, Jinbao Liu
BACKGROUND: Ubiquitin-proteasome system (UPS) is integral to cell survival by maintaining protein homeostasis, and its dysfunction has been linked to cancer and several other human diseases. Through counteracting ubiquitination, deubiquitinases (DUBs) can either positively or negatively regulate UPS function, thereby representing attractive targets of cancer therapies. Previous studies have shown that metal complexes can inhibit tumor growth through targeting the UPS; however, novel metal complexes with higher specificity for cancer therapy are still lacking...
December 5, 2018: EBioMedicine
Tineke W H Meijer, Wenny J M Peeters, Ludwig J Dubois, Marike W van Gisbergen, Rianne Biemans, Jan-Hendrik Venhuizen, Paul N Span, Johan Bussink
PURPOSE: Metabolic inhibition might sensitize tumors to irradiation. Here, we examined the effect of lonidamine (several metabolic effects, inhibiting hexokinase amongst others) and/or 968 (glutaminase inhibitor) on tumor cell metabolism, cell growth, cytotoxicity and radiosensitivity in NSCLC cell lines in vitro in relation to histology. MATERIALS AND METHODS: Adeno- (H23, HCC827, H1975) and squamous cell carcinoma (H520, H292, SW900) NSCLC cells were treated with lonidamine and/or 968 for 72 h under physiological levels of glucose (1...
December 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Yi-Long Wu, Victor Lee, Chong-Kin Liam, Shun Lu, Keunchil Park, Vichien Srimuninnimit, Jie Wang, Caicun Zhou, Anita Appius, Peter Button, Gregory Hooper, John F Palma, Katja Schulze, Sidney Scudder, David S Shames, Anny-Yue Yin, Guili Zhang, Tony Mok
OBJECTIVE: Patients with advanced non-small-cell lung cancer (NSCLC) with an adenocarcinoma component are recommended to undergo epidermal growth factor receptor (EGFR) mutation testing when being considered for EGFR targeted therapy. We conducted an exploratory analysis to inform the clinical utility of EGFR mutation testing in blood cell-free DNA using the cobas® EGFR Mutation Test v2. MATERIALS AND METHODS: Two EGFR mutation tests, a tissue-based assay (cobas® v1) and a tissue- and blood-based assay (cobas® v2) were used to analyze matched biopsy and blood samples (897 paired samples) from three Asian studies of first-line erlotinib with similar intent-to-treat populations...
December 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Mirjana Josipovic, Gitte Fredberg Persson, Jonas Scherman Rydhög, Bob Smulders, Jakob Borup Thomsen, Marianne Camille Aznar
PURPOSE: Evaluating performance of modern dose calculation algorithms in SBRT and locally advanced lung cancer radiotherapy in free breathing (FB) and deep inspiration breath hold (DIBH). METHODS: For 17 patients with early stage and 17 with locally advanced lung cancer, a plan in FB and in DIBH were generated with Anisotropic Analytical Algorithm (AAA). Plans for early stage were 3D-conformal SBRT, 45 Gy in 3 fractions, prescribed to 95% isodose covering 95% of PTV and aiming for 140% dose centrally in the tumour...
December 2018: Physica Medica: PM
Tatsuya Nagano, Motoko Tachihara, Yoshihiro Nishimura
Lung cancer is the leading cause of cancer death worldwide. Molecular targeted therapy has greatly advanced the field of treatment for non-small cell lung cancer (NSCLC), which accounts for the majority of lung cancers. Indeed, gefitinib, which was the first molecular targeted therapeutic agent, has actually doubled the survival time of NSCLC patients. Vigorous efforts of clinicians and researchers have revealed that lung cancer develops through the activating mutations of many driver genes including the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), v-Raf murine sarcoma viral oncogene homolog B (BRAF), and rearranged during transfection (RET) genes...
December 9, 2018: Current Cancer Drug Targets
Toke Printz Ringbæk, Uli Weber, Alina Santiago, Gheorghe Iancu, Andrea Wittig, Leszek Grzanka, Niels Bassler, Rita Engenhart-Cabillic, Klemens Zink
A ripple filter (RiFi) is a passive energy modulator used in scanned particle therapy to broaden the Bragg peak, thus lowering the number of accelerator energies required for homogeneous target coverage, which significantly reduces the irradiation time. As we have previously shown, a new 6 mm thick RiFi with 2D groove shapes produced with 3D printing can be used in carbon ion treatments with a similar target coverage and only a marginally worse planning conformity compared to treatments with in-use 3 mm thick RiFis of an older 1D design...
November 2, 2018: Physics in Medicine and Biology
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