Abnormal Anaplastic Lymphoma Kinase Research Articles

MET and ALK in glioblastoma multiforme (GBM): Comparison of IHC and FISH.

2021 Background: GBM, the most common and lethal malignant primary brain tumor in adults, has an overall one-year life expectancy of 33.7%. Personalized medicine on the basis of predictive biomarkers remains elusive in GBM; however a recent case report showed clinical improvement after treatment with a mesenchymal-epithelial transition (MET) inhibitor. The authors of that report ascribe clinical response to the MET inhibitor, but the drug is also an inhibitor of anaplastic lymphoma kinase (ALK). We explored the co-expression, gain, or amplification of both MET and ALK by IHC and FISH in GBM. Methods: A convenience sample of 56 available tumors from gross-resected GBM cases within the Duke Brain Tumor tissue bank was stained for MET using clone 8F11 (Leica) and for ALK using clone 5A4 (Novocastra). FISH employed the LSI ALK (2p23) breakpoint-spanning dual-color DNA probe and the LSI D7S486 (MET)/CEP 7 dual color DNA probe (Vysis). Results: Of 56 GBM cases, MET was expressed in 69.6% and ALK in 17.9% by IHC. By FISH, gain or amplification was found in 100% of cases for MET and in 48.2% for ALK. Co-expression of MET and ALK by IHC was 14.3% and 48.2% by FISH. Co-expression by either IHC or FISH was also 48.2%. OS estimation for this cohort is premature, with 77% of patients still alive. Conclusions: MET and ALK are (co-)expressed in a significant proportion of GBM. IHC detection of MET and ALK did not correlate well with FISH results, suggesting that gene gain or amplification does not necessarily lead to abnormal MET and ALK protein expression or that IHC methods or antibodies used can be optimized. Prior studies reported MET amplification in GBM as low as 4%. Our study indicates that MET gain/amplification and protein expression may be much higher, having implications for MET-targeted therapy. Additionally, co-expression of ALK and MET has implications for dual inhibitors of these signaling pathways as well as resistance mechanisms. Our continued work will explore significance of MET and ALK as predictors of therapeutic response, with careful control for clinically relevant patient and disease characteristics. [Table: see text]

New therapeutic agents marketed in the second half of 2011: Part 2

Abstract Objective To provide information regarding the most important properties of the new therapeutic agents marketed in the second half of 2011. Data sources Product labeling supplemented selectively with published studies and drug information reference sources. Data synthesis 13 new therapeutic agents were marketed in the United States during the second half of 2011, 6 of which were considered in part 1 of this two-part series. The other 7 agents are considered in this article: vemurafenib, vandetanib, ruxolitinib phosphate, crizotinib, brentuximab vedotin, belatacept, and deferiprone. Indications and information on dosage and administration for these agents are reviewed, as are the most important pharmacokinetic properties, drug interactions, and other precautions. Practical considerations for the use of these new agents are also discussed. When possible, the properties of the new drugs are compared with those of the older agents marketed for the same indications. Conclusion Five of the new drugs considered in this article are antineoplastic drugs that have properties that distinguish them from older agents. Vemurafenib is the second agent marketed in 2011 for the treatment of patients with unresectable or metastatic melanoma, joining ipilimumab. Vemurafenib is specifically indicated in patients with the BRAF V600E mutation (as detected by an FDA-approved test), which is present in approximately one-half of melanomas. Vandetanib is the first drug to be demonstrated to be effective in the treatment of patients with medullary thyroid cancer. Ruxolitinib is an inhibitor of Janus-associated kinases and is the first drug to be approved for the treatment of myelofibrosis, a rare disease involving the bone marrow. Crizotinib is the first drug to inhibit the kinase produced by the abnormal anaplastic lymphoma kinase (ALK) gene and has been approved for the treatment of patients with non–small-cell lung cancer that is ALK positive, as detected by an FDA-approved test. Brentuximab vedotin is the first drug to be approved for the treatment of systemic anaplastic large cell lymphoma and also is indicated for use in patients with Hodgkin's lymphoma following failure of other regimens. Two other agents are also considered in this article: belatacept acts as a selective T-cell (lymphocyte) costimulation blocker and is used in combination with other immunosuppressants for prophylaxis of organ rejection in adult patients receiving a kidney transplant. Deferiprone is an iron chelator that is administered orally for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.

Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

Anaplastic lymphoma kinase (ALK) was originally identified from a rare subtype of non-Hodgkin's lymphomas carrying t(2;5)(p23;q35) translocation, where ALK was constitutively activated as a result of a fusion with nucleophosmin (NPM). Aberrant ALK fusion proteins were also generated in inflammatory fibrosarcoma and a subset of non-small-cell lung cancers, and these proteins are implicated in their pathogenesis. Recently, ALK has been demonstrated to be constitutively activated by gene mutations and/or amplifications in sporadic as well as familial cases of neuroblastoma. Here we describe another mechanism of aberrant ALK activation observed in a neuroblastoma-derived cell line (NB-1), in which a short-form ALK protein (ALK(del2-3)) having a truncated extracellular domain is overexpressed because of amplification of an abnormal ALK gene that lacks exons 2 and 3. ALK(del2-3) was autophosphorylated in NB-1 cells as well as in ALK(del2-3)-transduced cells and exhibited enhanced in vitro kinase activity compared with the wild-type kinase. ALK(del2-3)-transduced NIH3T3 cells exhibited increased colony-forming capacity in soft agar and tumorigenicity in nude mice. RNAi-mediated ALK knockdown resulted in the growth suppression of ALK(del2-3)-expressing cells, arguing for the oncogenic role of this mutant. Our findings provide a novel insight into the mechanism of deregulation of the ALK kinase and its roles in neuroblastoma pathogenesis.

The potential for crizotinib in non-small cell lung cancer: a perspective review

Tyrosine kinases have a crucial role as key regulators of signaling pathways that influence cell differentiation and growth. Dysregulation of tyrosine kinase-mediated signaling is understood to be an important oncogenic driver. Genetic rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) gene occur in non-small cell lung cancer (NSCLC), anaplastic large cell lymphomoas, inflammatory myofibroblastic tumors, and other cancers. Cells with abnormal ALK signaling are sensitive to ALK inhibitors such as crizotinib. This review will highlight the discovery of the fusion between echinoderm microtubule-associated protein-like 4 (EML4) and ALK as an oncogenic driver, recognition of other ALK gene rearrangements in NSCLC, and the confirmation that crizotinib is an effective treatment for patients with ALK-positive NSCLC. Work is underway to further define the role for crizotinib in the treatment of ALK-positive lung cancer and other cancers and to investigate the molecular mechanisms for resistance to ALK inhibition with crizotinib.

Abstract 801: Clinical application of genomic signature including ALK mutation to the new tumor risk classification for neuroblastoma

Abstract Neuroblastoma (NBL) is one of the most common pediatric tumor arising from developing sympathetic nervous system. Its clinical and biological behavior is markedly heterogenous ranging from aggressive progression despite of intensive therapy to spontanous regression. NBL DNA shows complex patterns of genomic aberrations including MYCN amplification, deletion of chromosome 1p or 11q, and gain of chromosome 17q. We previously constructed the genomic subgrouping system of NBL based on the array CGH analysis for new tumor risk classification of NBL (Tomioka et al, Oncogene 2008). Analysis of 234 tumors by using 2,464 clones-BAC arrays demonstrated there exist three genomic groups (GG) of chromosomal aberrations in NBL: silent (S), partial gains and/or losses (P) and whole gains and/or losses (W). Each GG was further segregated into subgroups with different clinical outcomes clearly defined by MYCN amplification (MYCN-amp), 1p loss, 11q loss and 17q gain. Importantly, high-resolution array CGH analysis also led us to identify a novel genomic alteration in NBL, the activating mutation and amplification of anaplastic lymphoma kinase (ALK) oncogene on chromosome 2p23. In this study, to conduct the clinical validation of our GG risk classification system, array CGH and mutation analysis of ALK gene of 343 sporadic NBLs (stage 1: 48; stage2: 29; stage 4s: 27; stage 3: 60; stage 4: 179; median follow-up period is 78 months) were performed and the clinical impact of the genomic signatures was assessed. The results were fairly reproducible with our previous data, showing that GG-S or GG-W without MYCN-amp exhibited good prognosis (Ss and Ws, 8-year survival rates: >80%), while GG-P or GG-S accompanying MYCN-amp were very poor (Pa and Sa, 8-year survival rates: <35%). ALK gene abnormalities including mutations and amplification were found in 21 tumors in our dataset (6.1%), which caused fatal outcomes of the patients (p<0.01) especially those with MYCN-amp (ALKmut-/MYCNamp+, n=73 vs. ALKmut+/MYCNamp+, n=10, p=0.16). Interestingly, ALK abnormalities were frequently found in the certain genomic subgroups of the tumors, namely, GG-Pa with 1p loss, GG-Ps with 11q loss and GG-Ws with no partial 1p and 11q losses. These results suggested that the combination of genomic signatures with ALK abnormalities will further improve the potential of our tumor risk classification system of NBL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 801.

Inflammatory myofibroblastic tumor of the posterior mediastinum: an older adult case with anaplastic lymphoma kinase abnormalities determined using immunohistochemistry and fluorescence in situ hybridization

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm that usually occurs in children and young adults. Anaplastic lymphoma kinase (ALK) abnormalities in IMT, determined using immunohistochemistry and/or molecular genetic studies, including fluorescence in situ hybridization (FISH), have almost been limited to children and young adults. In elderly cases of IMT, these ALK abnormalities are very rare. We report on a case of IMT arising in the posterior mediastinum of a 59-year-old Japanese man that showed ALK abnormalities determined using immunohistochemistry and FISH, suggesting the neoplastic nature of a subset of IMTs in older patients similar to those in younger ones and the presence of an additional mechanism(s) that allows them to start to grow late.

Morphological and phenotypic features in pediatric large cell lymphoma and their correlation with ALK expression and the t(2;5)(p23;q35) translocation.

Anaplastic large cell lymphoma (ALCL) was proposed as a clinicopathologic entity over 14 years ago, but has been somewhat controversial due to the variability of its defining features and variable occurrence in different age-groups. To evaluate this entity in a pediatric population, 36 cases of childhood large cell lymphoma were evaluated for abnormalities of the anaplastic lymphoma kinase (ALK) gene that has been associated with ALCL morphology and immunophenotype. ALK abnormalities were evaluated by assay for the t(2;5)(p23;q35) translocation by RT-PCR and/or expression of NPM-ALK fusion protein by immunohistochemistry. Results showed 17 patients to have evidence of ALK gene expression. All of these children (mean age, 9.3 years) had tumors that were of T-cell phenotype (with the exception of a single case of null phenotype) and that expressed CD30. In contrast, 19 children with no evidence of ALK expression were older (mean, 12.7 years), and the majority (12/19) had tumors of B-cell phenotype. CD30 was also diffusely expressed in 8 of these 19 tumors. The difference in mean age between the two groups was statistically significant (P = 0.015). In three cases tested for both ALK and the t(2;5), ALK protein was detected in the absence of the t(2;5) translocation but no cases showed the reverse pattern, consistent with ALK fusion to genes other than NPM or activation of the ALK gene by another mechanism. These findings provide further support that ALK-positive ALCL is a distinct pathologic entity among pediatric large cell lymphomas primarily characterized by expression of T-cell markers, CD30, and EMA, and by a younger mean age.