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Zhong Ni, Xiting Wang, Tianchen Zhang, Rong Zhong Jin
Anaplastic lymphoma kinase (ALK) has become as an important target for the treatment of various human cancers, especially non-small-cell lung cancer. A mutation, F1174C, suited in the C-terminal helix αC of ALK and distal from the small-molecule inhibitor ceritinib bound to the ATP-binding site, causes the emergence of drug resistance to ceritinib. However, the detailed mechanism for the allosteric effect of F1174C resistance mutation to ceritinib remains unclear. Here, molecular dynamics (MD) simulations and binding free energy calculations [Molecular Mechanics/Generalized Born Surface Area (MM/GBSA)] were carried out to explore the advent of drug resistance mutation in ALK...
October 11, 2016: Computational Biology and Chemistry
Yoon Jin Cha, Hye Ryun Kim, Hyo Sup Shim
BACKGROUND: Clinical outcomes of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer according to ALK fusion variants are not clear. We aimed to investigate the prevalence of ALK fusion variants and to compare clinical outcomes according to ALK fusion variants. METHODS: A retrospective analysis was conducted on patients with advanced ALK-rearranged adenocarcinoma treated with chemotherapy and ALK inhibitors. ALK rearrangement was identified by fluorescence in situ hybridization and confirmed by immunohistochemistry...
October 19, 2016: Journal of Translational Medicine
Srividya Srinivasamaharaj, Bilal Khameze Salame, Jorge Rios-Perez, Goetz Kloecker, Cesar A Perez
The identification of anaplastic lymphoma kinase (ALK) gene rearrangements in subsets of non-small cell lung cancer patients has provided with unparalleled opportunities to hinder the progression of this disease through targeting the activity of these specific molecules. Unfortunately most patients develop disease progression in less than a year of treatment with crizotinib, the first-generation ALK-inhibitor. Areas covered: We review the resistance mechanisms to ALK inhibitors as well as an overview of the clinical activity of the alectinib, a second generation ALK inhibitor...
October 17, 2016: Expert Review of Anticancer Therapy
A S Mansfield, S J Murphy, F R Harris, S I Robinson, R S Marks, S H Johnson, J B Smadbeck, G C Halling, E S Yi, D Wigle, G Vasmatzis, J Jen
BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas that can occur at any age. Surgical resection is the primary treatment for patients with localized disease; however, these tumors frequently recur. Less commonly, patients with IMTs develop or present with metastatic disease. There is no standard of care for these patients and traditional cytotoxic therapy is largely ineffective. Most IMTs are associated with oncogenic ALK, ROS1 or PDGFRβ fusions and may benefit from targeted therapy...
October 14, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Trang H Au, Courtney C Cavalieri, David D Stenehjem
Clinical pharmacists are important contributors to the care of patients with cancer; it is therefore critical for oncology clinical pharmacists to stay current with new anticancer therapies. This review summarizes the epidemiology and pathogenesis of non-small cell lung cancer, including the most common genetic alterations, as well as the mechanism of action, clinical development, pharmacodynamics and pharmacokinetics of the anaplastic lymphoma kinase inhibitor ceritinib for the treatment of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer...
October 13, 2016: Journal of Oncology Pharmacy Practice
Masayoshi Miyawaki, Hiroyuki Yasuda, Tetsuo Tani, Junko Hamamoto, Daisuke Arai, Kota Ishioka, Keiko Ohgino, Shigenari Nukaga, Toshiyuki Hirano, Ichiro Kawada, Katsuhiko Naoki, Yuichiro Hayashi, Tomoko Betsuyaku, Kenzo Soejima
: Activation of the epidermal growth factor receptor (EGFR) pathway is one of the mechanisms inducing acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) such as crizotinib and alectinib. Ceritinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLCs) harboring the ALK gene rearrangement. However, the precise mechanism underlying acquired resistance to ceritinib is not well defined. This study set out to clarify the mechanism in ALK-translocated lung cancer and to find the preclinical rationale overcoming EGFR pathway-induced acquired resistance to ALK-TKIs...
October 5, 2016: Molecular Cancer Research: MCR
Emma D Deeks
Ceritinib (Zykadia™) is an oral, selective inhibitor of the anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase which, after genetic rearrangement, acts as an oncogenic driver in a proportion of non-small cell lung cancers (NSCLCs). The drug is approved in several countries worldwide for the treatment of patients with ALK-positive, advanced NSCLC who have previously received the first-generation ALK inhibitor crizotinib (indication details may vary by country). Approval was based on its clinical benefit in this setting in the phase I and II trials known as ASCEND-1 and -2...
October 2016: Targeted Oncology
Mengjia Qian, Bijun Zhu, Xiangdong Wang, Michael Liebman
Patients are diagnosed as anaplastic lymphoma kinase (ALK) positive, i.e. exhibiting the ALK rearrangement, and comprise 3-7% of non-small-cell lung cancer (NSCLC) cases. Three generations of ALK inhibitors have been developed and used in targeted therapy, although there are still improving spaces of drug resistance at the initiation of each treatment. The current review discusses the pathophysiology of ALK-positive NSCLC and the role of three generations of ALK target inhibitors including crizotinib, ceritinib, alectinib and lorlatinib, as well as the mechanisms of the secondary resistance...
September 29, 2016: Seminars in Cell & Developmental Biology
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
Sebastien Dejust, David Morland, Guillaume Fabre, Alain Prevost, Dimitri Papathanassiou
Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLC) account for 3% to 7% of all NSCLC and require a standard treatment by crizotinib. However, crizotinib resistance is frequent within the first 12 months of treatment. Ceritinib is a novel tyrosine kinase inhibitor of ALK recently introduced in France for metastatic or locally advanced crizotinib-resistant ALK NSCLC. We report the first use of ceritinib in our institution with a spectacular tumoral response after only 3 months of treatment...
November 2016: Clinical Nuclear Medicine
Jianzong Li, Wei Liu, Hao Luo, Jinku Bao
Anaplastic lymphoma kinase (ALK) plays a crucial role in multiple malignant cancers. It is known as a well-established target for the treatment of ALK-dependent cancers. Even though substantial efforts have been made to develop ALK inhibitors, only crizotinib, ceritinib, and alectinib had been approved by the U.S. Food and Drug Administration for patients with ALK-positive non-small cell lung cancer (NSCLC). The secondary mutations with drug-resistance bring up difficulties to develop effective drugs for ALK-positive cancers...
September 2016: Journal of Molecular Modeling
B Hallberg, R H Palmer
A vast array of oncogenic variants has been identified for anaplastic lymphoma kinase (ALK). Therefore, there is a need to better understand the role of ALK in cancer biology in order to optimise treatment strategies. This review summarises the latest research on the receptor tyrosine kinase ALK, and how this information can guide the management of patients with cancer that is ALK-positive. A variety of ALK gene alterations have been described across a range of tumour types, including point mutations, deletions and rearrangements...
September 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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
Alison C Johnson, Pascal Dô, Nicolas Richard, Catherine Dubos, Jean Jacques Michels, Jessica Bonneau, Radj Gervais
Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is sensitive to ALK inhibitor therapy, but resistance invariably develops and can be mediated by certain secondary mutations. The detection of these mutations is useful to guide treatment decisions, but tumors are not always easily accessible to re-biopsy. We report the case of a patient with ALK-rearranged NSCLC who presented acquired resistance to crizotinib and then alectinib. Sequencing analyses of DNA from a liver metastasis biopsy sample and circulating tumor DNA both found the same I1171N ALK kinase domain mutation, known to confer resistance to certain ALK inhibitors...
September 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
J Aubrey Waddell, Dominic A Solimando
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast...
July 2016: Hospital Pharmacy
Thomas E Stinchcombe
Targeted therapies have become standard therapies for patients with non-small cell lung cancer (NSCLC). A phase III trial of carboplatin and paclitaxel with and without bevacizumab in patients with advanced NSCLC with non-squamous histology demonstrated a statistically significant improvement in efficacy. In patients with NSCLC with an activating epidermal growth factor receptor (EGFR) mutation (defined as exon 19 deletion and exon 21 L858R point mutation), phase III trials of EGFR tyrosine kinase inhibitors (TKI) compared to platinum-based chemotherapy have demonstrated superior efficacy in the first-line setting...
2016: Cancer Treatment and Research
Zhuo Zhang, Hiroe Shiratsuchi, Nallasivam Palanisamy, Sunitha Nagrath, Nithya Ramnath
The emergence of liquid biopsy using circulating tumor cells (CTCs) as a resource to identify genomic alterations in cancer presents new opportunities for diagnosis, therapy and surveillance. The presented study identified EML4-ALK gene rearrangement in expanded CTCs from one ALK positive lung adenocarcinoma patient. At the time of radiographic progression, CTCs obtained from the patient revealed a drug resistance mutation, L1196M on the ALK gene. CTCs were expanded ex-vivo and drug sensitivity testing was performed using 2 ALK inhibitors, crizotinib and ceritinib...
August 6, 2016: Journal of Thoracic Oncology
György Losonczy
No abstract text is available yet for this article.
July 2016: Journal of Thoracic Disease
Ramon Andrade Bezerra De Mello, Davi Jing Jue Liu, Pedro N Aguiar, Hakaru Tadokoro
: Non-small cell lung cancer is the leading cancer-related cause of death. OBJECTIVE: We review the latest therapies for NSCLC with EGFR and ELM4-ALK mutations as well as the most relevant studies and promising patents. METHOD: A literature search of PubMed database was carried out to identify recent Clinical Trials using EGFR therapies and novel patents involving diagnosis and therapies on NSCLC. We conducted a search to find new therapy strategies, new biomarkers, and selected five patents we find relevant...
August 2, 2016: Recent Patents on Anti-cancer Drug Discovery
Geoffrey Liu, Jie Zhang, Zheng-Yi Zhou, Junlong Li, Xiaopeng Cai, James Signorovitch
OBJECTIVE: Time to progression (TTP) is a surrogate marker of overall survival (OS). However, OS is also dependent on post-progression survival (PPS). This study evaluated the association between TTP and the duration of PPS among adult patients who received ceritinib (Zykadia (1) ) for the treatment of advanced anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC). RESEARCH DESIGN AND METHODS: A pooled analysis was performed on 181 ASCEND-1 (phase I) and ASCEND-2 (phase II) patients who experienced disease progression while on ceritinib...
November 2016: Current Medical Research and Opinion
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