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Targeted therapy lung cancer

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https://www.readbyqxmd.com/read/29334371/cooperative-targeting-of-melanoma-heterogeneity-with-an-axl-antibody-drug-conjugate-and-braf-mek-inhibitors
#1
Julia Boshuizen, Louise A Koopman, Oscar Krijgsman, Aida Shahrabi, Elke Gresnigt- van den Heuvel, Maarten A Ligtenberg, David W Vredevoogd, Kristel Kemper, Thomas Kuilman, Ji-Ying Song, Nora Pencheva, Jens Thing Mortensen, Marnix Geukes Foppen, Elisa A Rozeman, Christian U Blank, Maarten L Janmaat, David Satijn, Esther C W Breij, Daniel S Peeper, Paul W H I Parren
Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29334189/a-multifunctional-micellar-nanoplatform-with-ph-triggered-cell-penetration-and-nuclear-targeting-for-effective-cancer-therapy-and-inhibition-to-lung-metastasis
#2
Yuting Jing, Xiang Xiong, Yang Ming, Jingya Zhao, Xing Guo, Guang Yang, Shaobing Zhou
The enhancement of cellular internalization and subsequent achievement of a nuclear targeting of nanocarriers play an important role in maximizing the therapeutic potency and minimizing the side effects of encapsulated drugs. Herein, a multifunctional micellar nanoplatform simultaneously with high cell penetration and nuclear targeting through pH-triggered surface charge reversal is presented. The miscellar system is constructed from poly(ethylene glycol)-poly(ε-caprolactone) with 2,3-dimethylmaleic anhydride-Tat decoration (PECL/DA-Tat)...
January 15, 2018: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/29333921/targeting-brd4-proteins-suppresses-the-growth-of-nsclc-through-downregulation-of-eif4e-expression
#3
Zhongyuan Gao, Ting Yuan, Xiao Zhou, Ping Ni, Geng Sun, Ping Li, Zhixiang Cheng, Xuerong Wang
Lung cancer is the leading cause of cancer-related death worldwide. Bromodomain and extraterminal domain (BET) proteins act as epigenome readers for gene transcriptional regulation. Among BET family members, BRD4 was well studied, but for its mechanism in non-small cell lung carcinoma has not been elucidated. eIF4E regulates gene translation and has been proved to play an important role in the progression of lung cancer. In this study, we first confirmed that BET inhibitors JQ1 and I-BET151 suppressed the growth of NSCLCs, in parallel with downregulated eIF4E expression...
January 15, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29332497/dosimetric-analysis-of-microscopic-disease-in-sbrt-for-lung-cancers
#4
Ronghu Mao, Lingling Tian, You Zhang, Lei Ren, Renqi Gao, Fang-Fang Yin, Hong Ge
OBJECTIVE: The objective of this study is to theoretically and experimentally evaluate the dosimetry in the microscopic disease regions surrounding the tumor under stereotactic body radiation therapy of lung cancer. METHODS: For simplicity, the tumor was considered moving along 1 dimension with a periodic function. The probability distribution function of the tumor position was generated according to the motion pattern and was used to estimate the delivered dose in the microscopic disease region...
December 2017: Technology in Cancer Research & Treatment
https://www.readbyqxmd.com/read/29332448/helical-therapy-is-safe-for-lung-stereotactic-body-radiation-therapy-despite-limitations-in-achieving-sharp-dose-gradients
#5
Neha P Amin, Adrian Nalichowski, Shauna Campbell, Jal Hyder, Robyn Spink, Andre A Konski, Michael Dominello
PURPOSE: We observed that many of our helical therapy lung stereotactic body radiation therapy plans did not meet the Radiation Therapy Oncology Group (RTOG) recommended R50% (volume of 50% of the prescription dose/planning target volume), which characterizes the steepness of dose fall off. We hypothesized that despite not meeting R50%, helical therapy lung stereotactic body radiation therapy plans would confer similar local control and minimal side effects as previously reported using nonhelical treatment platforms...
December 2017: Technology in Cancer Research & Treatment
https://www.readbyqxmd.com/read/29331646/progress-in-the-management-of-advanced-thoracic-malignancies-in-2017
#6
REVIEW
Roberto Ferrara, Laura Mezquita, Benjamin Besse
The treatment paradigm of non-small cell lung cancer (NSCLC) underwent a major revolution during the course of 2017. Immune checkpoint inhibitors (ICIs) brought remarkable improvements in response and overall survival (OS) both in unselected pretreated patients and in untreated patients with PD-L1 expression ≥50%. Furthermore, compelling preliminary results were reported for new combinations of anti-PD-1/PD-L1 agents with chemotherapy or anti-CTLA4 inhibitors. The success of the ICIs appeared to extend to patients with small cell lung cancer (SCLC), mesothelioma or thymic tumors...
January 10, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29331452/design-synthesis-and-evaluation-of-%C3%AE-turn-mimetics-as-lsd1-selective-inhibitors
#7
Yosuke Ota, Shin Miyamura, Misaho Araki, Yukihiro Itoh, Shusuke Yasuda, Mitsuharu Masuda, Tomoyuki Taniguchi, Yoshihiro Sowa, Toshiyuki Sakai, Kenichiro Itami, Junichiro Yamaguchi, Takayoshi Suzuki
Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity...
January 2, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29331419/the-therapeutic-potential-of-human-adipose-derived-mesenchymal-stem-cells-producing-cxcl10-in-a-mouse-melanoma-lung-metastasis-model
#8
Hamed Mirzaei, Hossein Salehi, Reza Kazemi Oskuee, Ali Mohammadpour, Hamid Reza Mirzaei, Mohammad Reza Sharifi, Reza Salarinia, Hossein Yousofi Darani, Mojgan Mokhtari, Aria Masoudifar, Amirhossein Sahebkar, Rasoul Salehi, Mahmoud Reza Jaafari
Interferon γ-induced protein 10 kDa (IP-10) is a potent chemoattractant and has been suggested to enhance antitumor activity and mediate tumor regression through multiple mechanisms of action. Multiple lines of evidence have indicated that genetically-modified adult stem cells represent a potential source for cell-based cancer therapy. In the current study, we assessed therapeutic potential of human adipose derived mesenchymal stem cells (hADSC) genetically-modified to express IP-10 for the treatment of lung metastasis in an immunocompetent mouse model of metastatic melanoma...
January 10, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29329112/master-protocols-in-lung-cancer-experience-from-lung-master-protocol
#9
Vincent K Lam, Vassiliki Papadimitrakopoulou
PURPOSE OF REVIEW: Contemporary advances in the understanding of the molecular and immunologic basis of metastatic lung cancer have firmly changed its treatment paradigm to a personalized, biomarker-driven approach. However, the majority of lung-cancer patients [especially lung squamous cell carcinoma (LUSC)] still do not have effective targeted therapeutic options. Master protocols, such as Lung-MAP, represent an innovative clinical trial approach designed to accelerate evaluation of novel biomarker-driven therapies...
January 10, 2018: Current Opinion in Oncology
https://www.readbyqxmd.com/read/29327716/genomic-heterogeneity-of-alk-fusion-breakpoints-in-non-small-cell-lung-cancer
#10
Jason N Rosenbaum, Ryan Bloom, Jason T Forys, Jeff Hiken, Jon R Armstrong, Julie Branson, Samantha McNulty, Priya D Velu, Kymberlie Pepin, Haley Abel, Catherine E Cottrell, John D Pfeifer, Shashikant Kulkarni, Ramaswamy Govindan, Eric Q Konnick, Christina M Lockwood, Eric J Duncavage
In lung adenocarcinoma, canonical EML4-ALK inversion results in a fusion protein with a constitutively active ALK kinase domain. Evidence of ALK rearrangement occurs in a minority (2-7%) of lung adenocarcinoma, and only ~60% of these patients will respond to targeted ALK inhibition by drugs such as crizotinib and ceritinib. Clinically, targeted anti-ALK therapy is often initiated based on evidence of an ALK genomic rearrangement detected by fluorescence in situ hybridization (FISH) of interphase cells in formalin-fixed, paraffin-embedded tissue sections...
January 12, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29325801/editorial-the-role-of-medical-physics-in-lung-sbrt
#11
EDITORIAL
Pietro Mancosu, Andrew Nisbet, Núria Jornet
Stereotactic body radiation therapy (SBRT) has become a standard treatment for non-operable patients with early stage non-small cell lung cancer (NSCLC). In this context, medical physics community has largely helped in the starting and the growth of this technique. In fact, SBRT requires the convergence of many different features for delivering large doses in few fractions to small moving target in an heterogeneous medium. The special issue of last month, was focused on the different physics challenges in lung SBRT...
January 9, 2018: Physica Medica: PM
https://www.readbyqxmd.com/read/29325035/amplicon-based-next-generation-sequencing-of-plasma-cell-free-dna-for-detection-of-driver-and-resistance-mutations-in-advanced-non-small-cell-lung-cancer
#12
N Guibert, Y Hu, N Feeney, Y Kuang, V Plagnol, G Jones, K Howarth, J F Beeler, C P Paweletz, G R Oxnard
Background: Genomic analysis of plasma cell-free DNA is transforming lung cancer care, however available assays are limited by cost, turnaround time, and imperfect accuracy. Here we study amplicon-based plasma next-generation sequencing (NGS), rather than hybrid-capture-based plasma NGS, hypothesizing this would allow sensitive detection and monitoring of driver and resistance mutations in advanced non-small cell lung cancer (NSCLC). Methods: Plasma samples from patients with NSCLC and a known targetable genotype (EGFR, ALK/ROS1 and other rare genotypes) were collected while on therapy and analyzed, blinded to tumor genotype...
January 9, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29324317/tincr-suppresses-proliferation-and-invasion-through-regulating-mir-544a-fbxw7-axis-in-lung-cancer
#13
Xiaochun Liu, Jing Ma, Feng Xu, Li Li
BACKGROUND: Long noncoding RNAs (LncRNAs) play critical roles in multiple biological processes implicated in the development and progression of cancers. Terminal differentiation-induced lncRNA (TINCR) has been demonstrated to be associated with the carcinogenesis of several cancers. However, little is known about the function and mechanism of TINCR in lung cancer. METHODS: qRT-PCR was performed to measure the expression of TINCR, miR-544a or FBXW7 mRNA in lung cancer tissues or cells...
January 8, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29324212/managing-patients-with-oligometastatic-non-small-cell-lung-cancer
#14
Sarah Jo Stephens, Michael J Moravan, Joseph K Salama
Metastatic lung cancer has long been considered incurable, with the goal of treatment being palliation. However, a clinically meaningful number of these patients with limited metastases (approximately 25%) are living long term after definitive treatment to all sites of active disease. These patients with so-called oligometastatic disease likely represent a distinct clinical group who may possess a more indolent biology compared with their more widely metastatic counterparts. Hellman and Weichselbaum proposed the existence of the oligometastatic state, on the basis of the spectrum theory of cancer spread...
January 2018: Journal of Oncology Practice
https://www.readbyqxmd.com/read/29322408/protocols-to-evaluate-cigarette-smoke-induced-lung-inflammation-and-pathology-in-mice
#15
Ross Vlahos, Steven Bozinovski
Cigarette smoking is a major cause of chronic obstructive pulmonary disease (COPD). Inhalation of cigarette smoke causes inflammation of the airways, airway wall remodelling, mucus hypersecretion and progressive airflow limitation. Much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and infectious (viral and bacterial) exacerbations (AECOPD). Comorbidities, in particular skeletal muscle wasting, cardiovascular disease and lung cancer markedly impact on disease morbidity, progression and mortality...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29321536/enzymes-of-the-one-carbon-folate-metabolism-as-anticancer-targets-predicted-by-survival-rate-analysis
#16
Jun Koseki, Masamitsu Konno, Ayumu Asai, Hugh Colvin, Koichi Kawamoto, Naohiro Nishida, Daisuke Sakai, Toshihiro Kudo, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii
The significance of mitochondrial metabolism in cancer cells has recently been gaining attention. Among other findings, One-carbon folate metabolism has been reported to be closely associated with cellular characteristics in cancer. To study molecular targets for efficient cancer therapy, we investigated the association between the expressions of genes that code enzymes involved in one-carbon metabolism and survival rate of patients with adenocarcinomas of the colorectum and lung. Patients with high expression of genes that control the metabolic cycle of tetrahydrofolate (THF) in mitochondria, SHMT2, MTHFD2, and ALDH1L2, have a shorter overall survival rate compared with patients with low expression of these genes...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29321482/enhanced-yap-expression-leads-to-egfr-tki-resistance-in-lung-adenocarcinomas
#17
Ting-Fang Lee, Yu-Chi Tseng, Phung Anh Nguyen, Yu-Chuan Li, Chao-Chi Ho, Cheng-Wen Wu
Epidermal growth factor receptor (EGFR) mutation is prevalently expressed in lung adenocarcinoma cases and acts as one of the major driving oncogenes. EGFR tyrosine kinase inhibitors (TKIs) have been used in patients with EGFR-mutant as an effective targeted therapy in lung adenocarcinoma, but drug resistance and tumor recurrence inevitably occurs. Recently, Yes-associate protein (YAP) has been reported to promote multiple cancer cell properties, such as promoting cell proliferation, epithelial-mesenchymal transition and drug resistance...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29320312/targeted-therapy-for-advanced-solid-tumors-on-the-basis-of-molecular-profiles-results-from-mypathway-an-open-label-phase-iia-multiple-basket-study
#18
John D Hainsworth, Funda Meric-Bernstam, Charles Swanton, Herbert Hurwitz, David R Spigel, Christopher Sweeney, Howard Burris, Ron Bose, Bongin Yoo, Alisha Stein, Mary Beattie, Razelle Kurzrock
Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study...
January 10, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29318404/does-alk-rearrangement-predict-favorable-response-to-the-therapy-of-bevacizumab-plus-pemetrexed-in-advanced-non-small-cell-lung-cancer-case-report-and-literature-review
#19
Zhichao Liu, Youting Bao, Butuo Li, Xindong Sun, Linlin Wang
BACKGROUND: Advanced ALK-rearranged non-small cell lung cancer (NSCLC) patients will develop acquired resistance after anaplastic lymphoma kinase (ALK) inhibitors therapies. Vascular endothelial growth factor-A (VEGF-A) production and tumor vessel formation were found to be more significantly enriched in ALK-rearrangement NSCLC than that in epidermal growth factor receptor or Kirsten rat sarcoma viral oncogene mutated NSCLC. However, the correlation between ALK rearrangement and the efficacy of bevacizumab (a recombinant humanized IgG1 monoclonal antibody targeting VEGF-A) was still elusive...
January 9, 2018: Clinical and Translational Medicine
https://www.readbyqxmd.com/read/29317428/small-cell-transformation-of-alk-rearranged-non-small-cell-adenocarcinoma-of-the-lung
#20
Agnes Balla, Kenneth J Hampel, Farrah Khan, Dara L Aisner, Nikoletta Sidiropoulos
Anaplastic lymphoma kinase (ALK) gene rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). These rearrangements occur because of a chromosomal inversion within the short arm of chromosome 2, which results in the formation of the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion oncogene. While NSCLC transformation to SCLC is a rare phenomenon described in EGFR mutant cancers primarily after treatment with targeted therapy, it is exceedingly rare in ALK rearranged adenocarcinomas (Toyokawa et al...
January 9, 2018: Cold Spring Harbor Molecular Case Studies
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