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The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Crizotinib (XalkoriTM), developed by Pfizer, is an anticancer agent acting as an ALK (Anaplastic Lymphoma Kinase) and ROS1 (c-Ros Oncogene 1) inhibitor. It is approved by the FDA for treatment of non-small-cell lung carcinoma (NSCLC) in the US, and is undergoing clinical trials for safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children. It competitively binds to the ATP-binding pocket of target kinases. In 2011, the FDA approved crizotinib (XalkoriTM) to treat certain late-stage (locally advanced or metastatic) non-small-cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene. Approval required the availability of a companion molecular test for the EML4-ALK fusion gene.
EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Francisco E. Vera-Badillo, Janet E. Dancey
In 2007, Soda and colleagues identified a “driver mutation” in a very small subset of patients with NSCLC: the fusion between the 5’ portion of EML4 (echinoderm microtubule-associated like-protein 4) and the 3’ portion of ALK (anaplastic lymphoma kinase) [8]. The importance of this discovery is highlighted by new agents that target this unique chimeric protein. In this chapter, we will review the biology and treatment of EML4-ALK and other ALK gene rearrangements in NSCLC.
Overview of Companion Diagnostics (CDx) for Precision Medicine
Published in Il-Jin Kim, Companion Diagnostics (CDx) in Precision Medicine, 2019
Lung cancer has the second highest number of approved CDx assays, with fifteen (Fig. 1.2). Since the identification of EGFR mutations and its inhibitors,23,24 NSCLC, along with breast cancer, has been the best example of the use of targeted or tailored therapies. EML4-ALK fusion was also identified in NSCLC patients in 2007.13 ALK inhibitor, which was developed before EML4-ALK was identified, was approved in 2011 for treatment of NSCLC in patients who have EML4-ALK fusion.25 It took only four years from biomarker identification to the FDA approval.25 This may be the best example of “repurposing” or “reassignment” of drugs with a newly identified biomarker. Recently, immunotherapy that targets neoantigens is shedding light on new anti-cancer drug development. Anti-PD-1 immunotherapy was recently approved for treating NSCLC with positive PD-L1 protein level.8, 11,12
Anaplastic lymphoma kinase inhibitors: an updated patent review (2014–2018)
Published in Expert Opinion on Therapeutic Patents, 2020
Yi-Min Liu, Chun-Nan Kuo, Jing-Ping Liou
The deregulation of ALK activity is consequently one of the major mechanisms of human carcinogenesis. Since the first translocation of ALK in ALCL was discovered, other ALK rearrangements have also been identified in various cancers such as lymphoma, myofibroblastic tumors, and non-small cell lung cancer (Table 1) [18–20]. The NMP-ALK fusion gene is the most frequently found in the ALCL with a 70–80% occurrence [21–24]. TPM3-ALK and TPM4-ALK are displayed in inflammatory myofibroblastic tumors (IMT) with a frequency of about 20% [25–27]. In 2007, the EML4-ALK was discovered as the first oncogenic fusion in non-small cell lung cancer (NSCLC). Although it represents only 5% of NSCLC cases, the number of ALK-positive NSCLC patients appears to be much higher, based on the total incidence of lung cancer worldwide [28–30]. With other cancers, like thyroid cancers, even though their frequency is low, several fusion genes, such as STRN-ALK have been reported [31,32].
Origins and clinical relevance of proteoforms in pediatric malignancies
Published in Expert Review of Proteomics, 2019
Amanda Lorentzian, Anuli Uzozie, Philipp F. Lange
IHC assays can also be a valuable tool in the clinic due to their high sensitivity and high throughput ability. IHC assays are used to detect protein markers in biopsies to support cancer diagnosis, prognosis, and monitoring [141]. For example, Mino-kinudson et al. (2010) utilized IHC assays to assess specific ALK rearrangements in adenocarcinomas [142]. These EML4-ALK fusions are found in approximately 5% of the lung adenocarcinomas and could be a potential target for therapy. Using novel highly sensitive antibody ALK they were able to detect ALK rearrangements with increased sensitivity and reliability that has potential to be routinely applied in the clinic [142]. Although they have many advantages, some limitations of IHC assays include the efficiency of antibodies, limited specificity, and cross-reactivity of the antibodies [140].
Targeted therapies in non-small cell lung cancer: a focus on ALK/ROS1 tyrosine kinase inhibitors
Published in Expert Review of Anticancer Therapy, 2018
Assunta Sgambato, Francesca Casaluce, Paolo Maione, Cesare Gridelli
ALK rearrangements define an important molecular subgroup of the disease reported in 3–5% of all patients with NSCLC and in 33% of EGFR negative never smokers. Firstly, in 2007, Soda and colleagues discovered the ALK gene rearrangement with EML4 in NSCLC: this rearrangement led to an in-frame fusion protein with oncogenic activity in vitro. The EML4-ALK protein thus contained the amino-terminal half of EML4 and the intracellular catalytic domain of ALK. This region of EML4 results in constitutive dimerization of the kinase domain of ALK leading to aberrant activation of downstream signaling such as Akt, STAT3, and extracellular signal regulated kinase 1 and 2 (ERK1/2) [1]. Subsequently, several EML4-ALK variants have been identified in NSCLC, but clinical significance of each variant is still unknown.