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Yiqiang OuYang, Wensheng Zou, Liang Peng, Zunhua Yang, Qidong Tang, Mengzi Chen, Shuang Jia, Hong Zhang, Zhou Lan, Pengwu Zheng, Wufu Zhu
Eight series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and PC-3). Most of the forty nine target compounds showed excellent antiproliferative activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, MCF-7 and PC-3 cancer cell lines, with the IC50 values of 1.09 ± 0.04 μM, 1.34 ± 0.13 μM and 1.23 ± 0...
May 9, 2018: European Journal of Medicinal Chemistry
Renata Duchnowska, Sibylle Loibl, Jacek Jassem
Approximately 30-50% of advanced HER2-positive breast cancer patients will develop central nervous system (CNS) metastases, with an annual risk of around 10%, and a half of them will die from brain progression. An increased risk of brain metastases is also seen in patients with early HER2-positive breast cancer administered curative therapy. Brain metastases in HER2-positive breast cancer patients usually constitute the first site of recurrence. The administration of anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, considerably delays the onset of symptomatic brain disease: however, the limited penetration of these compounds into the CNS hinders their efficacy...
May 9, 2018: Cancer Treatment Reviews
Mário L de Lemos, Brittney Mathers, Nadine Badry, Linda Hamata, Kelly Lo
Afatinib, trametinib and regorafenib are three costly oral oncology drugs with a short shelf-life after the original container has been opened. Their short shelf-lives are due to degradation on exposure to moisture. Therefore, manufacturers recommend them to be dispensed in the original packaging with the desiccant. However, the prescribed quantities do not always match the quantities in the original packaging, usually because of dose modifications for toxicities. This leads to potentially significant drug wastage and financial losses...
January 1, 2018: Journal of Oncology Pharmacy Practice
Cheng-Han Yu, Chi-Chi Chou, Hsin-Fang Tu, Wei-Chieh Huang, Ya-Yeh Ho, Kay-Hooi Khoo, Ming-Shyue Lee, Geen-Dong Chang
Afatinib, used for the first-line treatment of non-small-cell lung carcinoma (NSCLC) patients with distinct epidermal growth factor receptor (EGFR) mutations, inactivates EGFR by mimicking ATP structure and forming a covalent adduct with EGFR. We developed a method to unravel potential targets of afatinib in NSCLC cells through immunoprecipitation of afatinib-labeling proteins with anti-afatinib antiserum and mass spectrometry analysis. Ribonucleotide reductase (RNR) is one of target proteins of afatinib revealed by this method...
April 20, 2018: Oncotarget
Jordi Codony-Servat, Silvia García-Roman, Miguel Ángel Molina-Vila, Jordi Bertran-Alamillo, Ana Giménez-Capitán, Santiago Viteri, Andrés F Cardona, Erik d'Hondt, Niki Karachaliou, Rafael Rosell
INTRODUCTION: Mutations in EGFR correlate with impaired response to immune checkpoint inhibitors and the development of novel immunotherapeutic approaches for EGFR mutant non-small cell lung cancer (NSCLC) is of particular interest. Immunization against EGF has demonstrated efficacy in a phase III trial including unselected NSCLC patients, but little was known about the mechanisms involved in the effects of the anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) or their activity in tumor cells with EGFR mutations...
May 8, 2018: Journal of Thoracic Oncology
Chulaporn Limwattananon, Supon Limwattananon, Onanong Waleekhachonloet, Thananan Rattanachotphanit
OBJECTIVES: Tyrosine kinase inhibitors (TKIs) have shown to be better for progression-free survival than chemotherapy as the first-line treatment for advanced, non-small cell lung cancer (NSCLC), especially in patients with epidermal growth factor receptor mutation (EGFR M+). This study evaluates under the Thai health system context, cost-effectiveness of (A) the use of platinum doublets for all without EGFR testing, and (B) an EGFR test followed by TKIs or platinum doublets conditional on test results...
June 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Hua Duan, Yanmei Peng, Huijuan Cui, Yuqin Qiu, Qiang Li, Jingyi Zhang, Wen Shen, Chenyao Sun, Chufan Luo
Epidermal growth factor receptor-tyrosine kinase inhibitors have improved progression-free survival and overall survival in non-small-cell lung cancer (NSCLC) patients with sensitive mutations. However, response of uncommon mutation to epidermal growth factor receptor-tyrosine kinase inhibitors is still unclear. S768I is one of the uncommon mutations. A female patient with advanced NSCLC with a single S768I mutation achieved effectiveness from afatinib after showing no response to gefitinib. The patient had progression-free survival after taking afatinib for 6 months, and her follow-up is continuing...
2018: OncoTargets and Therapy
Paulina Kozakiewicz, Ludmiła Grzybowska-Szatkowska
Despite the development of standard therapies, including surgery, radiotherapy and chemotherapy, survival rates for head and neck squamous cell carcinoma (HNSCC) have not changed significantly over the past three decades. Complete recovery is achieved in <50% of patients. The treatment of advanced HNSCC frequently requires multimodality therapy and involves significant toxicity. The promising, novel treatment option for patients with HNSCC is molecular-targeted therapies. The best known targeted therapies include: Epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab, panitumumab, zalutumumab and nimotuzumab), EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, lapatinib, afatinib and dacomitinib), vascular endothelial growth factor (VEGF) inhibitor (bevacizumab) or vascular endothelial growth factor receptor (VEGFR) inhibitors (sorafenib, sunitinib and vandetanib) and inhibitors of phosphatidylinositol 3-kinase/serine/threonine-specific protein kinase/mammalian target of rapamycin...
May 2018: Oncology Letters
Florian Lüke, Raquel Blazquez, Rezan Fahrioglu Yamaci, Xin Lu, Benedikt Pregler, Stefan Hannus, Karin Menhart, Dirk Hellwig, Hans-Jürgen Wester, Saskia Kropf, Daniel Heudobler, Jirka Grosse, Jutta Moosbauer, Markus Hutterer, Peter Hau, Markus J Riemenschneider, Michaela Bayerlová, Annalen Bleckmann, Bernhard Polzer, Tim Beißbarth, Christoph A Klein, Tobias Pukrop
Brain and leptomeningeal metastasis (LMM) of non-small cell lung cancer is still associated with poor prognosis. Moreover, the current diagnostic standard for LMM often yields false negative results and the scientific progress in this field is still unsatisfying. We present a case of a 71-year old patient with an isolated LMM. While standard diagnostics could only diagnose a cancer of unknown primary, the use of [68 Ga]-Pentixafor-PET/CT (CXCR4-PET/CT, a radiotracer targeting CXCR4) and a liquid biopsy of the cerebrospinal fluid revealed the primary NSCLC...
April 10, 2018: Oncotarget
Takayuki Shiroyama, Shingo Nasu, Ayako Tanaka, So Takata, Kentaro Masuhiro, Hiromune Takada, Satomu Morita, Naoko Morishita, Hidekazu Suzuki, Norio Okamoto, Kunimitsu Kawahara, Tomonori Hirashima
Acquiring resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is inevitable. Transformation to small cell lung cancer (SCLC) is reported as a possible mechanism of this acquired resistance. We describe the case of a 35-year-old man with lung adenocarcinoma harboring EGFR exon 19 deletion. After 7 months of successful treatment with afatinib, he experienced relapse and rebiopsy revealed SCLC with EGFR exon 19 deletion. Tumor marker tests at this point showed normal levels of serum neuron-specific enolase and pro-gastrin releasing peptide...
2018: Respiratory Medicine Case Reports
Takayuki Kaburagi, Moriyuki Kiyoshima, Takeshi Nawa, Hideo Ichimura, Takefumi Saito, Kenji Hayashihara, Hideyasu Yamada, Hiroaki Satoh, Takeo Endo, Yoshihisa Inage, Kazuhito Saito, Masaharu Inagaki, Nobuyuki Hizawa, Yukio Sato, Hiroichi Ishikawa, Mitsuaki Sakai, Koichi Kamiyama, Norihiro Kikuchi, Hiroyuki Nakamura, Kinya Furukawa, Takahide Kodama, Takaaki Yamashita, Akihiro Nomura, Susumu Yoshida
AIM: To describe the prevalence and determinants of acquired epidermal growth factor receptor (EGFR) T790M gene mutation in a clinical practice setting. MATERIALS AND METHODS: We performed a retrospective chart review study between January 2013 and November 2017 across multiple institutes, covering a population of 3 million people. RESULTS: We reviewed the charts of 233 patients non-small cell lung cancer with EGFR mutations. Of them, 99 (42...
May 2018: Anticancer Research
Benedikt Kramer, Marcel Kneissle, Richard Birk, Nicole Rotter, Christoph Aderhold
BACKGROUND/AIM: Therapeutic options of locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC) are limited. Src and cKIT are key protein regulators for local tumor progression. The aim of the study was to investigate the therapeutic potential of targeted therapies in human squamous cell carcinoma (HNSCC) in vitro. Therefore, the influence of the selective tyrosine kinase inhibitors niotinib, dasatinib, erlotinib, gefitinib and afatinib on Src and cKIT expression in Human papilloma virus (HPV)-positive and HPV-negative squamous cancer cells (SCC) was analyzed in vitro...
May 2018: Anticancer Research
Ichiro Sakanoue, Hiroshi Hamakawa, Reiko Kaji, Yukihiro Imai, Nobuyuki Katakami, Yutaka Takahashi
Afatinib, the second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been postulated to be associated with improved inhibition of EGFR-dependent tumor growth compared with first-generation EGFR-TKIs for advanced non-small cell lung cancer (NSCLC). We present a case of lung adenocarcinoma (cT3N0M0) treated with neoadjuvant afatinib and sleeve lobectomy. Because of the location of the tumor, reduced FEV1 value, and the presence of EGFR mutation, the patient was planned to be prescribed afatinib (30 mg daily) for 3 weeks as neoadjuvant therapy and underwent sleeve lobectomy to avoid pneumonectomy as much as possible...
March 2018: Journal of Thoracic Disease
Léon C van Kempen, Hangjun Wang, Maria Leonor Aguirre, Alan Spatz, Goulnar Kasymjanova, Juliana F Vilacha, Matthew R Groves, Jason Agulnik, David Small
No abstract text is available yet for this article.
April 25, 2018: Journal of Thoracic Oncology
Ken Uchibori, Naohiko Inase, Makoto Nishio, Naoya Fujita, Ryohei Katayama
INTRODUCTION: The survival of patients with EGFR mutation-positive lung cancer has dramatically improved since the introduction of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Recently, osimertinib showed significantly prolonged progression-free survival than first-generation EGFR-TKI in first-line treatment, suggesting that a paradigm change that would move osimetinib to first-line treatment is indicated. We performed N-ethyl-N-nitrosourea (ENU) mutagenesis screening to uncover the resistant mechanism in first- and second-line osimertinib treatment...
April 24, 2018: Journal of Thoracic Oncology
Bianca van Veggel, Adrianus J de Langen, Sayed Hashemi, Kim Monkhorst, Daniëlle A M Heideman, Erik Thunnissen, Egbert F Smit
INTRODUCTION: Epidermal growth factor receptor (EGFR) exon 20 insertions comprise 4-9% of EGFR mutated non-small-cell lung cancer (NSCLC). Despite being an oncogenic driver, they are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). We hypothesized that dual EGFR blockade with afatinib, an irreversible EGFR TKI, and cetuximab, a monoclonal antibody against EGFR, could induce tumor responses. METHODS: Four patients with EGFR exon 20 insertion positive NSCLC were treated with afatinib 40 mg once daily and cetuximab 250-500 mg/m2 every two weeks...
April 24, 2018: Journal of Thoracic Oncology
Maximilian Hochmair
Brain metastases and/or leptomeningeal disease (LMD) with associated central nervous system (CNS) metastases are known complications of advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). It is important, therefore, to assess the activity of EGFR tyrosine kinase inhibitors (TKIs) versus such CNS complications. This review explores the literature reporting the intracranial activity of EGFR TKIs, and finds that there is evidence for varying efficacy of the approved agents, erlotinib, gefitinib, afatinib, and osimertinib in patients with CNS metastases...
April 27, 2018: Targeted Oncology
Alessandra Bisagni, Maria Pagano, Sally Maramotti, Francesca Zanelli, Martina Bonacini, Elena Tagliavini, Luca Braglia, Massimiliano Paci, Andrea Mozzarelli, Stefania Croci
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib, erlotinib and afatinib) are indicated as first-line therapy in patients with non-small cell lung cancer (NSCLC) whose tumors harbor activating mutations in the EGFR gene. Erlotinib is also used in second and third-line therapy for patients whose tumors have wild type EGFR but to date there are no validated biomarkers useful to identify which patients may benefit from this treatment. The expression level of four miRNAs: miR-133b, -146a, -7 and -21 which target EGFR was investigated by real-time PCR in tumor specimens from NSCLC patients treated with erlotinib administered as the second or third line...
2018: PloS One
Miao Wang, Alex Yuang-Chi Chang
Epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) is the first choice of treatment for advanced non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, single agent usually has limited efficacy due to heterogeneous resistant mechanisms of cancer cells. Thus drug combination therapy would offer more benefits by synergistic interactions and avoidance of resistance emergence. In this study, we selected 8 NSCLC cell lines with different genetic characteristics as research models to investigate the efficacy of 4 agents (gefitinib, cetuximab, afatinib and dasatinib) and their combinations...
March 27, 2018: Oncotarget
Shivangi Awasthi, Tapan Maity, Benjamin L Oyler, Yue Qi, Xu Zhang, David R Goodlett, Udayan Guha
Lung cancer causes the highest mortality among all cancers. Patients harboring kinase domain mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors (TKIs), however, acquired resistance always develops. Moreover, 30-40% of patients with EGFR mutations exhibit primary resistance. Hence, there is an unmet need for additional biomarkers of TKI sensitivity that complement EGFR mutation testing and predict treatment response. We previously identified phosphopeptides whose phosphorylation is inhibited upon treatment with EGFR TKIs, erlotinib and afatinib in TKI sensitive cells, but not in resistant cells...
April 13, 2018: Journal of Proteomics
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