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https://www.readbyqxmd.com/read/27915169/replacing-the-terminal-piperidine-in-ceritinib-with-aliphatic-amines-confers-activities-against-crizotinib-resistant-mutants-including-g1202r
#1
Gangadhar Rao Mathi, Chung Hyo Kang, Heung Kyoung Lee, Raghavendra Achary, Ha-Yeon Lee, Joo-Youn Lee, Jae Du Ha, Sunjoo Ahn, Chi Hoon Park, Chong Ock Lee, Jong Yeon Hwang, Chang-Soo Yun, Hee Jung Jung, Sung Yun Cho, Hyoung Rae Kim, Pilho Kim
The piperidine fragment in ceritinib was replaced with diverse aliphatic amines to improve inherent resistance issues of ceritinib. While most of the prepared compounds exhibit as similar in vitro activities as ceritinib, compound 10 shows encouraging activities against wild-type ALK as well as crizotinib-resistant mutants including extremely resistant G1202R mutant with an IC50 of 1.8 nM. Furthermore, pharmacokinetic profiles of 10 is apparently better than that of ceritinib. In murine xenograft studies, compound 10 turns out to be as active as ceritinib, suggesting that further optimization of 10 may lead to clinical candidates overcoming ALK mutant issues...
November 24, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27912826/diagnosis-and-treatment-of-anaplastic-lymphoma-kinase-positive-non-small-cell-lung-cancer
#2
REVIEW
Kathryn C Arbour, Gregory J Riely
Anaplastic lymphoma kinase (ALK) gene rearrangements occur in a small portion of patients with non-small cell lung cancer (NSCLC). These gene rearrangements lead to constitutive activation of the ALK kinase and subsequent ALK-driven tumor formation. Patients with tumors harboring such rearrangements are highly sensitive to ALK inhibitors, such as crizotinib, ceritinib, and alectinib. Resistance to these kinase inhibitors occurs through several mechanisms, resulting in ongoing clinical challenges. This review summarizes the biology of ALK-positive lung cancer, methods for diagnosing ALK-positive NSCLC, current FDA-approved ALK inhibitors, mechanisms of resistance to ALK inhibition, and potential strategies to combat resistance...
February 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/27899405/brigatinib-effective-in-alk-nsclc
#3
(no author information available yet)
Results from a phase I/II trial indicate that the investigational ALK inhibitor brigatinib is active in patients with ALK-rearranged non-small cell lung cancer. Patients who had previously received crizotinib-as well as those who hadn't-responded to the drug, which was also active in patients with brain metastases.
November 29, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27888620/identification-of-different-alk-mutations-in-a-pair-of-neuroblastoma-cell-lines-established-at-diagnosis-and-relapse
#4
Lindi Chen, Angharad Humphreys, Lisa Turnbull, Angela Bellini, Gudrun Schleiermacher, Helen Salwen, Susan L Cohn, Nick Bown, Deborah A Tweddle
Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor kinase that belongs to the insulin receptor superfamily and has previously been shown to play a role in cell proliferation, migration and invasion in neuroblastoma. Activating ALK mutations are reported in both hereditary and sporadic neuroblastoma tumours, and several ALK inhibitors are currently under clinical evaluation as novel treatments for neuroblastoma. Overall, mutations at codons F1174, R1275 and F1245 together account for ~85% of reported ALK mutations in neuroblastoma...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27879019/screening-for-alk-abnormalities-in-central-nervous-system-metastases-of-non-small-cell-lung-cancer-alk-abnormalities-in-cns-metastases-of-nsclc
#5
Marcin Nicoś, Bożena Jarosz, Paweł Krawczyk, Kamila Wojas-Krawczyk, Tomasz Kucharczyk, Marek Sawicki, Juliusz Pankowski, Tomasz Trojanowski, Janusz Milanowski
Anaplastic lymphoma kinase (ALK) gene rearrangement was reported in 3-7% of primary non-small-cell lung cancer (NSCLC) and its presence is commonly associated with adenocarcinoma (AD) type and non-smoking history. ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib and ceritinib showed efficiency in patients with primary NSCLC harboring ALK gene rearrangement. Moreover, response to ALK TKIs was observed in central nervous system (CNS) metastatic lesions of NSCLC. However, there are no reports concerning the frequency of ALK rearrangement in CNS metastases...
November 23, 2016: Brain Pathology
https://www.readbyqxmd.com/read/27877008/detection-of-alk-translocation-in-non-small-cell-lung-carcinoma-nsclc-and-its-clinicopathological-significance-using-the-ventana-immunohistochemical-staining-method-a-single-center-large-scale-investigation-of-1-504-chinese-han-patients
#6
Lin Yang, Yun Ling, Lei Guo, Di Ma, Xuemin Xue, Bingning Wang, Junling Li, Jianming Ying
OBJECTIVE: The novel fully automated immunohistochemistry (IHC) assay-Ventana anaplastic lymphoma kinase (ALK)-D5F3 for screening ALK rearrangements has been approved by China's Food and Drug Administration in 2013, our previous study disclosed a highly specificity and sensitivity nearly 100%, and its efficacy needs to be evaluated in a large cohort of primary lung adenocarcinoma patients, and to compare clinicopathological features with ALK (+) and ALK (-) lung adenocarcinoma. METHODS: A total of 1,504 consecutive surgical lung adenocarcinoma cases of Chinese Han population were collected and re-diagnosed according to the 2011 multidisciplinary classification of lung adenocarcinoma...
October 2016: Chinese Journal of Cancer Research, Chung-kuo Yen Cheng Yen Chiu
https://www.readbyqxmd.com/read/27874172/development-of-crizotinib-a-rationally-designed-tyrosine-kinase-inhibitor-for-non-small-cell-lung-cancer
#7
REVIEW
Candice C Poon, John J Kelly
Non-small cell lung cancer (NSCLC) is the number one cause of global mortality. Despite aggressive treatment, the prognosis is dismal. Patients with advanced NSCLC have a median survival of four months from the time of diagnosis. Fortunately, molecularly-based approaches to drug discovery have yielded a tyrosine kinase inhibitor, crizotinib, which significantly prolongs median progression free survival in a subset of patients. Although initial clinical trial results demonstrate crizotinib has a promising role to play in NSCLC treatment, development of resistance leaves much to be elucidated about how to effectively combat this deadly disease...
November 22, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27872098/systematic-drug-screening-identifies-tractable-targeted-combination-therapies-in-triple-negative-breast-cancer
#8
Vikram B Wali, Casey G Langdon, Matthew A Held, James T Platt, Gauri A Patwardhan, Anton Safonov, Bilge Aktas, Lajos Pusztai, David F Stern, Christos Hatzis
Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation. Medium-throughput results were scrutinized and extensively analyzed for sensitivity patterns, synergy, anticancer activity and validation in low-throughput experiments...
November 21, 2016: Cancer Research
https://www.readbyqxmd.com/read/27867635/efficacy-of-crizotinib-in-alk-fusion-variants
#9
COMMENT
Tetsu Kobayashi, Hajime Fujimoto, Esteban C Gabazza
No abstract text is available yet for this article.
October 2016: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/27865624/w-alk-into-the-next-stage
#10
REVIEW
Gouji Toyokawa, Takashi Seto, Mitsuhiro Takenoyama, Yukito Ichinose
In 2007, the rearrangement of anaplastic lymphoma kinase (ALK) was identified to be associated with the pathogenesis of a subset of patients with non-small-cell lung cancer (NSCLC). Surprisingly, approximately 4 years after the discovery of ALK rearrangement in lung cancer, the first-in-class ALK inhibitor (ALKi), crizotinib, was approved for metastatic ALK-rearranged NSCLC by the US Food and Drug Administration. Subsequently, next-generation ALKis, such as alectinib and ceritinib, have been developed, and some of them have been applied in the clinical setting...
October 26, 2016: Clinical Lung Cancer
https://www.readbyqxmd.com/read/27863911/crizotinib-for-ros1-patients-one-small-step-in-biomarker-testing-one-giant-leap-for-advanced-nsclc-patients
#11
EDITORIAL
Oscar Juan, Sanjay Popat
No abstract text is available yet for this article.
November 11, 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27863497/next-generation-sequencing-facilitates-detection-of-the-classic-e13-a20-eml4-alk-fusion-in-an-alk-fish-ihc-inconclusive-biopsy-of-a-stage-iv-lung-cancer-patient-a-case-report
#12
Anna-Lena Volckmar, Volker Endris, Farastuk Bozorgmehr, Clemens Lier, Carlota Porcel, Martina Kirchner, Jonas Leichsenring, Roland Penzel, Michael Thomas, Peter Schirmacher, Arne Warth, Albrecht Stenzinger
BACKGROUND: Inhibition of the oncogenic fusion-gene EML4-ALK is a current first-line approach for patients with stage IV non-small cell lung cancer. While FISH was established as the gold standard for identifying these patients, there is accumulating evidence that other methods of detection, i.e., immunohistochemistry and next-generation sequencing (NGS), exist that may be equally successful. However, the concordance of these methods is under investigation. CASE PRESENTATION: Adding to the current literature, we here report a 56 year old female never-smoker with stage IV lung adenocarcinoma whose biopsy was IHC and FISH inconclusive but positive in NGS...
November 18, 2016: Diagnostic Pathology
https://www.readbyqxmd.com/read/27863201/pooled-analysis-of-cns-response-to-alectinib-in-two-studies-of-pretreated-patients-with-alk-positive-non-small-cell-lung-cancer
#13
Shirish M Gadgeel, Alice T Shaw, Ramaswamy Govindan, Leena Gandhi, Mark A Socinski, D Ross Camidge, Luigi De Petris, Dong-Wan Kim, Alberto Chiappori, Denis L Moro-Sibilot, Michael Duruisseaux, Lucio Crino, Tommaso De Pas, Eric Dansin, Antje Tessmer, James Chih-Hsin Yang, Ji-Youn Han, Walter Bordogna, Sophie Golding, Ali Zeaiter, Sai-Hong Ignatius Ou
Purpose Alectinib has shown activity in the CNS in phase I and II studies. To further evaluate this activity, we pooled efficacy and safety data from two single-arm phase II studies (NP28761 and NP28673; ClinicalTrials.gov identifiers: NCT01871805 and NCT01801111, respectively) in patients with ALK-positive non-small-cell lung cancer (NSCLC). Patients and Methods Both studies included patients with ALK-positive NSCLC who had previously received crizotinib; all patients received alectinib 600 mg twice per day...
December 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27836716/activity-and-safety-of-brigatinib-in-alk-rearranged-non-small-cell-lung-cancer-and-other-malignancies-a-single-arm-open-label-phase-1-2-trial
#14
Scott N Gettinger, Lyudmila A Bazhenova, Corey J Langer, Ravi Salgia, Kathryn A Gold, Rafael Rosell, Alice T Shaw, Glen J Weiss, Meera Tugnait, Narayana I Narasimhan, David J Dorer, David Kerstein, Victor M Rivera, Timothy Clackson, Frank G Haluska, David Ross Camidge
BACKGROUND: Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers of non-small-cell lung cancer (NSCLC). Brigatinib (AP26113) is an investigational ALK inhibitor with potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors. We aimed to assess brigatinib in patients with advanced malignancies, particularly ALK-rearranged NSCLC. METHODS: In this ongoing, single-arm, open-label, phase 1/2 trial, we recruited patients from nine academic hospitals or cancer centres in the USA and Spain...
November 7, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27836576/establishment-of-a-conditional-transgenic-mouse-model-recapitulating-eml4-alk-positive-human-non-small-cell-lung-cancer
#15
Kyoung Ho Pyo, Sun Min Lim, Hye Ryun Kim, Young Hoon Sung, Mi Ran Yun, Sung-Moo Kim, Hwan Kim, Han Na Kang, Ji Min Lee, Sang Gyun Kim, Chae Won Park, Hyun Chang, Hyo Sup Shim, Han-Woong Lee, Byoung Chul Cho
BACKGROUND: ALK fusion is a distinct molecular subclassification of non-small-cell lung cancer (NSCLC) that is targeted by ALK inhibitors. We established a transgenic mouse model that expresses tumors highly resembling human NSCLC harboring EML-ALK fusion. We aimed to test EML4-ALK transgenic mouse model as a platform for assessing efficacy of ALK inhibitor and examining mechanisms of acquired resistance to ALK inhibitor. MATERIALS AND METHODS: Transgenic mouse lines harboring LoxP-STOP-LoxP- FLAG tagged human EML4-ALK (variant 1) transgene was established using C57BL/6N mice...
November 8, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27835868/clinical-data-from-the-real-world-efficacy-of-crizotinib-in-chinese-patients-with-advanced-alk-rearranged-non-small-cell-lung-cancer-and-brain-metastases
#16
Puyuan Xing, Shouzheng Wang, Xuezhi Hao, Tongtong Zhang, Junling Li
Brain metastasis in non small cell lung cancer (NSCLC) patients is often considered as a terminal stage of advanced disease. Crizotinib is a small-molecule tyrosine kinase inhibitor (TKI) for ALK-rearranged NSCLC patients. Herein, we conducted a retrospective study to explore how Crizotinib affects the control of brain metastases and the overall prognosis in advanced ALK-rearranged NSCLC patients with brain metastases in Chinese population. A total of 34 patients were enrolled, of whom 20 (58.8%) patients had baseline brain metastases before Crizotinib treatment...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27835601/is-there-a-benefit-of-first-or-second-line-crizotinib-in-locally-advanced-or-metastatic-anaplastic-lymphoma-kinase-positive-non-small-cell-lung-cancer-a-meta-analysis
#17
Hao Hu, Wei Qing Lin, Qian Zhu, Xiong Wen Yang, Hai Dong Wang, Yu Kang Kuang
BACKGROUND: Crizotinib show a promising efficacy in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). However, differences in efficacy for first- and second-line crizotinib are unclear. RESULTS: The pooled overall response rate and progression-free survival were 65% and 9.38 months, respectively. In the subgroup analysis, first-line crizotinib showed a higher trend of overall response rate and longer trend of progression-free survival although there was no statistical difference between first-line and second-line crizotinib (74%, 11...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27831000/targeted-therapies-for-the-treatment-of-non-small-cell-lung-cancer-monoclonal-antibodies-and-biological-inhibitors
#18
Ana P S Silva, Priscila V Coelho, Maristella Anazetti, Patricia U Simioni
The usual treatments for patients with non-small-cell lung cancer (NSCLC), such as advanced lung adenocarcinoma, are unspecific and aggressive, and include lung resection, radiotherapy and chemotherapy. Recently, treatment with monoclonal antibodies and biological inhibitors has emerged as an effective alternative, generating effective results with few side effects. In recent years, several clinical trials using monoclonal antibodies presented potential benefits to NSCLC, and four of them are already approved for the treatment of NSCLC, such as cetuximab, bevacizumab, nivolumab and pembrolizumab...
November 10, 2016: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/27811184/coupling-an-eml4-alk-centric-interactome-with-rna-interference-identifies-sensitizers-to-alk-inhibitors
#19
Guolin Zhang, Hannah Scarborough, Jihye Kim, Andrii I Rozhok, Yian Ann Chen, Xiaohui Zhang, Lanxi Song, Yun Bai, Bin Fang, Richard Z Liu, John Koomen, Aik Choon Tan, James Degregori, Eric B Haura
Patients with lung cancers harboring anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors, but acquired resistance inevitably arises. A better understanding of proximal ALK signaling mechanisms may identify sensitizers to ALK inhibitors that disrupt the balance between prosurvival and proapoptotic effector signals. Using affinity purification coupled with mass spectrometry in an ALK fusion lung cancer cell line (H3122), we generated an ALK signaling network and investigated signaling activity using tyrosine phosphoproteomics...
October 18, 2016: Science Signaling
https://www.readbyqxmd.com/read/27804873/recent-development-in-the-discovery-of-anaplastic-lymphoma-kinase-alk-inhibitors-for-non-small-cell-lung-cancer
#20
Jingru Liu, Shutao Ma
Non-Small Cell Lung Cancer (NSCLC) is an especially aggressive cancer, the optimal drugs for which are still being developed. The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. EML4-ALK fusion gene initially identified in patients with NSCLC in 2007 is defined as a new molecular subset, which is highly sensitive to ALK inhibition. Since the first ALK inhibitor, crizotinib, was approved by the US Food and Drug Administration (FDA) for the treatment of NSCLC patients in 2011, ALK has been identified as a promising target for NSCLC therapy...
October 29, 2016: Current Medicinal Chemistry
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