ceritinib and Lymphoma--Large-Cell--Anaplastic

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Female; Humans; Lymphoma, Large-Cell, Anaplastic; Male; Middle Aged; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Outcome; Young Adult

More than 80% of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients harbor the (nucleophosmin) NPM1-ALK fusion gene t(2;5) chromosomal translocation. We evaluated the preclinical and clinical efficacy of ceritinib treatment of this aggressive lymphoma.. We studied the effects of ceritinib treatment in NPM1-ALK+ T-cell lymphoma cell lines in vitro and on tumor size and survival advantage in vivo utilizing tumor xenografts. We treated an NPM1-ALK+ ALCL patient with ceritinib. We reviewed all hematologic malignancies profiled by a large hybrid-capture next-generation sequencing (NGS)-based comprehensive genomic profiling assay for ALK alterations.. In our in vitro experiments, ceritinib inhibited constitutive activation of the fusion kinase NPM1-ALK and downstream effector molecules STAT3, AKT, and ERK1/2, and induced apoptosis of these lymphoma cell lines. Cell cycle analysis following ceritinib treatment showed G0/G1 arrest with a concomitant decrease in the percentage of cells in S and G2/M phases. Further, treatment with ceritinib in the NPM1-ALK+ ALCL xenograft model resulted in tumor regression and improved survival. Of 19 272 patients with hematopoietic diseases sequenced, 58 patients (0.30%) harbored ALK fusions that include histiocytic disorders, multiple myeloma, B-cell neoplasms, Castleman's disease, and juvenile xanthogranuloma. A multiple relapsed NPM1-ALK+ ALCL patient treated with ceritinib achieved complete remission with ongoing clinical benefit to date, 5 years after initiation of therapy.. This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies.

Topics: Anaplastic Lymphoma Kinase; Humans; Lymphoma, Large-Cell, Anaplastic; Nucleophosmin; Prospective Studies; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

We report herein the discovery of a class of potent small-molecule inhibitors of anaplastic lymphoma kinase (ALK) containing a fused indoloquinoline scaffold. The most promising compound CJ-2360 has an IC

Topics: Administration, Oral; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Disease Progression; Drug Discovery; Female; Humans; Lymphoma, Large-Cell, Anaplastic; Mice; Mice, SCID; Protein Kinase Inhibitors; Structure-Activity Relationship; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described.

Topics: 4-Aminopyridine; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Crystallography, X-Ray; Drug Design; Half-Life; Humans; Lymphoma, Large-Cell, Anaplastic; Mice; Mice, SCID; Microsomes, Liver; Molecular Dynamics Simulation; Protein Kinase Inhibitors; Protein Structure, Tertiary; Rats; Receptor Protein-Tyrosine Kinases; Structure-Activity Relationship; Transplantation, Heterologous