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https://www.readbyqxmd.com/read/27682212/current-and-developing-therapies-for-the-treatment-of-non-small-cell-lung-cancer-with-alk-abnormalities-update-and-perspectives-for-clinical-practice
#1
M Caccese, R Ferrara, S Pilotto, L Carbognin, G Grizzi, A Caliò, M Brunelli, F Cuppone, S Petraglia, A Scarpa, G Tortora, E Bria
The treatment of patients with ALK-rearranged non-small-cell lung cancer was completely revolutionized by the introduction of Crizotinib, a small molecule inhibiting ALK, MET and ROS1. Given that resistance occurs within approximately 12 months, in order to develop more potent inhibitors and to increase drug penetration to CNS, innovative ALK-inhibitors were developed. Second-generation ALK inhibitors Ceritinib (LDK378), Alectinib (CH5424802/RO5424802) and Brigatinib (AP26113) have shown significant clinical activity, and were rapidly approved by regulatory agencies...
October 8, 2016: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/27565932/drastic-initial-response-and-subsequent-response-to-two-alk-inhibitors-in-a-patient-with-a-highly-aggressive-alk-rearranged-inflammatory-myofibroblastic-tumor-arising-in-the-pleural-cavity
#2
Akira Ono, Haruyasu Murakami, Masakuni Serizawa, Kazushige Wakuda, Hirotsugu Kenmotsu, Tateaki Naito, Tetsuhiko Taira, Yasuhiro Koh, Yasuhisa Ohde, Takashi Nakajima, Masahiro Endo, Toshiaki Takahashi
A 57-year-old male current smoker was diagnosed with an aggressive variant of ALK-rearranged inflammatory myofibroblastic tumor (IMT) arising in the pleural cavity. First line treatment with ASP3026 was initiated at a dose of 125mg once daily. A follow-up CT scan revealed drastic regression of the pleural lesion. After disease progression with ASP3026 treatment, LDK378 (ceritinib) was initiated at a dose of 750mg once daily. A follow-up CT scan revealed a second drastic regression of the pleural lesion. Furthermore, it is noteworthy that this case represents the use of serum hyaluronan levels to assist in monitoring of treatment efficacy in an IMT...
September 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27413712/tackling-alk-in-non-small-cell-lung-cancer-the-role-of-novel-inhibitors
#3
REVIEW
Francesco Facchinetti, Marcello Tiseo, Massimo Di Maio, Paolo Graziano, Emilio Bria, Giulio Rossi, Silvia Novello
Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds...
June 2016: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/27197808/crizotinib-primary-resistance-overcome-by-ceritinib-in-a-patient-with-alk-rearranged-non-small-cell-lung-cancer
#4
Francesco Facchinetti, Caroline Caramella, Nathalie Auger, David Planchard, Julien Adam, Ludovic Lacroix, Jordi Remon, Christophe Massard, Jean-Charles Soria, Luc Friboulet, Benjamin Besse
We report on the case of a patient affected by advanced non-small cell lung cancer (NSCLC) harboring an anaplastic lymphoma kinase (ALK) gene rearrangement who did not respond to crizotinib but subsequently benefited from treatment with ceritinib (LDK378). Although second-generation ALK inhibitors have shown activity in patients pretreated with crizotinib who experienced secondary resistance, this is the first report to date describing their efficacy in a case of primary resistance. Of note, none of the previously described molecular mechanisms explaining resistance to crizotinib was detected on either the initial or post-crizotinib biopsies...
May 13, 2016: Tumori
https://www.readbyqxmd.com/read/26712094/discovery-of-novel-tetrahydroisoquinoline-containing-pyrimidines-as-alk-inhibitors
#5
Raghavendra Achary, Jeong In Yun, Chi Min Park, Gangadhar Rao Mathi, Joo Yun Lee, Jae Du Ha, Chong Hak Chae, 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
Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378...
January 15, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/26616860/alk-inhibitor-resistance-in-alk-f1174l-driven-neuroblastoma-is-associated-with-axl-activation-and-induction-of-emt
#6
D N Debruyne, N Bhatnagar, B Sharma, W Luther, N F Moore, N-K Cheung, N S Gray, R E George
The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT)...
July 14, 2016: Oncogene
https://www.readbyqxmd.com/read/26556876/effect-of-ceritinib-ldk378-on-enhancement-of-chemotherapeutic-agents-in-abcb1-and-abcg2-overexpressing-cells-in-vitro-and-in-vivo
#7
Jing Hu, Xu Zhang, Fang Wang, Xiaokun Wang, Ke Yang, Meng Xu, Kenneth K W To, Qingshan Li, Liwu Fu
Multidrug resistance (MDR) is the leading cause of treatment failure in cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2, play a key role in mediating MDR by pumping anticancer drugs out from cancer cells. Ceritinib (LDK378) is a second-generation tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) currently in phase III clinical trial for the treatment of non-small cell lung cancer. Here, we found that ceritinib remarkably enhanced the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 over-expressing cancer cells in vitro and in vivo...
December 29, 2015: Oncotarget
https://www.readbyqxmd.com/read/26020125/phase-i-study-of-ceritinib-ldk378-in-japanese-patients-with-advanced-anaplastic-lymphoma-kinase-rearranged-non-small-cell-lung-cancer-or-other-tumors
#8
MULTICENTER STUDY
Makoto Nishio, Haruyasu Murakami, Atsushi Horiike, Toshiaki Takahashi, Fumihiko Hirai, Naoko Suenaga, Takeshi Tajima, Kota Tokushige, Masami Ishii, Anthony Boral, Matthew Robson, Takashi Seto
INTRODUCTION: Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK inhibitors, but resistance develops. This study assessed the maximum-tolerated dose, safety, pharmacokinetics (PK), and antitumor activity of ceritinib, a novel ALK inhibitor (ALKi), in Japanese patients with ALK-rearranged malignancies. METHODS: This phase I, multicenter, open-label study (NCT01634763) enrolled adult patients with ALK-rearranged (by fluorescence in situ hybridization and/or immunohistochemistry) locally advanced/metastatic malignancy that had progressed despite standard therapy...
July 2015: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/25795812/o10-1next-generation-alk-inhibitors-and-mechanisms-of-resistance-to-therapy
#9
J Gainor
Anaplastic lymphoma kinase (ALK) gene rearrangements are important therapeutic targets in non-small cell lung cancer (NSCLC) that impart sensitivity to treatment with ALK tyrosine kinase inhibitors (TKIs), such as crizotinib. Indeed, crizotinib is now considered a standard of care for ALK-positive NSCLC patients based upon randomized trials in which crizotinib produced significant improvements in objective response rate (ORR) and progression-free survival (PFS) compared to first- and second-line cytotoxic chemotherapy...
March 2015: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/25539610/-current-status-of-targeted-therapy-for-anaplastic-lymphoma-kinase-in-non-small-cell-lung-cancer
#10
REVIEW
Li Ma, Shucai Zhang
The rate of the anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC) tissues is 3%-5%. The first-in-class ALK tyrosine kinase inhibitor, crizotinib, can effectively target these tumors represent a significant advance in the evolution of personalized medicine for NSCLC. A randomized phase III clinical trial in which superiority of crizotinib over chemotherapy was seen in previously treated ALK-positive NSCLC patients demonstrated durable responses and well tolerance in the majority of ALK-positive NSCLC patients treated with crizotinib...
December 2014: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/25458559/ceritinib-ldk378-a-potent-alternative-to-crizotinib-for-alk-rearranged-non-small-cell-lung-cancer
#11
REVIEW
Sen Li, Xiaolong Qi, Yufeng Huang, Dingfeng Liu, Fangyu Zhou, Caicun Zhou
The success in identifying the chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) as an oncogenic driver has thoroughly changed the treatment of non-small-cell lung cancer. In the past decade, targeted drugs have emerged as an efficient personalized strategy for ALK-rearranged non-small-cell lung cancer. The accelerated approval of potent ALK inhibitors, such as crizotinib and more recently ceritinib (LDK378), based on the well designed phase I/II trials has been a landmark success in clinical cancer research and contributes a new era of oncogenic targeted therapy characterized by elegant clinical trial design...
March 2015: Clinical Lung Cancer
https://www.readbyqxmd.com/read/25349307/alectinib-shows-potent-antitumor-activity-against-ret-rearranged-non-small-cell-lung-cancer
#12
Tatsushi Kodama, Toshiyuki Tsukaguchi, Yasuko Satoh, Miyuki Yoshida, Yoshiaki Watanabe, Osamu Kondoh, Hiroshi Sakamoto
Alectinib/CH5424802 is a known inhibitor of anaplastic lymphoma kinase (ALK) and is being evaluated in clinical trials for the treatment of ALK fusion-positive non-small cell lung cancer (NSCLC). Recently, some RET and ROS1 fusion genes have been implicated as driver oncogenes in NSCLC and have become molecular targets for antitumor agents. This study aims to explore additional target indications of alectinib by testing its ability to inhibit the activity of kinases other than ALK. We newly verified that alectinib inhibited RET kinase activity and the growth of RET fusion-positive cells by suppressing RET phosphorylation...
December 2014: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/25302162/review-of-the-current-targeted-therapies-for-non-small-cell-lung-cancer
#13
REVIEW
Kim-Son H Nguyen, Joel W Neal, Heather Wakelee
The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others...
October 10, 2014: World Journal of Clinical Oncology
https://www.readbyqxmd.com/read/25258420/ceritinib-a-new-tyrosine-kinase-inhibitor-for-non-small-cell-lung-cancer
#14
REVIEW
Maryann R Cooper, Helen Chim, Hoyi Chan, Cheryl Durand
OBJECTIVE: To review ceritinib for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small-cell lung cancer (NSCLC). DATA SOURCES: Literature searches were conducted in PubMed, EMBASE (1974 to July week 5, 2014), and Google Scholar using the terms ceritinib, LDK378, and non-small-cell lung cancer. STUDY SELECTION AND DATA EXTRACTION: One phase 1 trial and 2 abstracts were identified. DATA SYNTHESIS: Ceritinib is approved for the treatment of ALK-positive metastatic NSCLC in patients who are intolerant to or have progressed despite therapy with crizotinib...
January 2015: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/25157781/ldk378-compassionate-use-for-treating-carcinomatous-meningitis-in-an-alk-translocated-non-small-cell-lung-cancer
#15
Jennifer Arrondeau, Samy Ammari, Benjamin Besse, Jean-Charles Soria
No abstract text is available yet for this article.
August 2014: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/25135623/clinical-challenges-in-targeting-anaplastic-lymphoma-kinase-in-advanced-non-small-cell-lung-cancer
#16
REVIEW
Namrata Vijayvergia, Ranee Mehra
The revolution in individualized therapy for patients with advanced non-small cell lung cancer (NSCLC) has seen the emergence of a number of molecularly targeted therapies for distinct patient molecular subgroups. Activating anaplastic lymphoma kinase (ALK)-gene rearrangement has been detected in 3-7 % of NSCLC cases, and the ALK inhibitor crizotinib is now an approved treatment for patients with tumors harboring this event. However, resistance to ALK-targeted therapies is a ubiquitous problem in the management of advanced ALK-positive NSCLC and can be mediated by secondary kinase mutations or the activation of compensatory alternative oncogenic drivers...
September 2014: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/24889366/alk-inhibitors-and-advanced-non-small-cell-lung-cancer-review
#17
REVIEW
Antonio Rossi, Paolo Maione, Paola Claudia Sacco, Assunta Sgambato, Francesca Casaluce, Marianna Luciana Ferrara, Giovanni Palazzolo, Fortunato Ciardiello, Cesare Gridelli
Treatment of unselected patients with advanced non-small cell lung cancer (NSCLC) receiving third-generation platinum-based chemotherapy has reached a plateau of effectiveness. Histology and molecular analyses are the cornerstone in the initial diagnosis of NSCLC and are key determinants to address the appropriate strategy of treatment. In non-squamous histology the combination of cisplatin plus pemetrexed or carboplatin plus paclitaxel plus bevacizumab are considered today the best regimens yielding better activity and efficacy...
August 2014: International Journal of Oncology
https://www.readbyqxmd.com/read/24675041/the-alk-inhibitor-ceritinib-overcomes-crizotinib-resistance-in-non-small-cell-lung-cancer
#18
Luc Friboulet, Nanxin Li, Ryohei Katayama, Christian C Lee, Justin F Gainor, Adam S Crystal, Pierre-Yves Michellys, Mark M Awad, Noriko Yanagitani, Sungjoon Kim, AnneMarie C Pferdekamper, Jie Li, Shailaja Kasibhatla, Frank Sun, Xiuying Sun, Su Hua, Peter McNamara, Sidra Mahmood, Elizabeth L Lockerman, Naoya Fujita, Makoto Nishio, Jennifer L Harris, Alice T Shaw, Jeffrey A Engelman
UNLABELLED: Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, ceritinib (LDK378), in the setting of crizotinib resistance. An interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of patients with crizotinib-resistant NSCLC, revealed that ceritinib potently overcomes crizotinib-resistant mutations...
June 2014: Cancer Discovery
https://www.readbyqxmd.com/read/24623980/development-of-anaplastic-lymphoma-kinase-alk-inhibitors-and-molecular-diagnosis-in-alk-rearrangement-positive-lung-cancer
#19
REVIEW
Eiji Iwama, Isamu Okamoto, Taishi Harada, Koichi Takayama, Yoichi Nakanishi
The fusion of echinoderm microtubule-associated protein-like 4 with anaplastic lymphoma kinase (ALK) was identified as a transforming gene for lung cancer in 2007. This genetic rearrangement accounts for 2%-5% of non-small-cell lung cancer (NSCLC) cases, occurring predominantly in younger individuals with adenocarcinoma who are never- or light smokers. A small-molecule tyrosine-kinase inhibitor of ALK, crizotinib, was rapidly approved by the US Food and Drug Administration on the basis of its pronounced clinical activity in patients with ALK rearrangement-positive NSCLC...
2014: OncoTargets and Therapy
https://www.readbyqxmd.com/read/24598368/overcoming-the-resistance-to-crizotinib-in-patients-with-non-small-cell-lung-cancer-harboring-eml4-alk-translocation
#20
REVIEW
Cesar A Perez, Michel Velez, Luis E Raez, Edgardo S Santos
The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets. In 2011, regulatory entities granted conditional approval to an anaplastic lymphoma kinase inhibitor (crizotinib) based on an impressive overall response rate in previously treated non-small cell lung cancer patients whose tumors harbored EML4/ALK translocations...
May 2014: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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