pyrimidinones and Gallbladder-Neoplasms

Gemcitabine-based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second-line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non-competitive inhibitor of MEK1/MEK2. In this phase IIa open-label, single-arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine-based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12-week non-PD rate. Secondary assessments included safety, progression-free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non-PD rate at week 12 was 10% (95% confidence interval, 1.2-31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6-12.1) and 1-year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end-point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss-of-function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864.

Topics: Administration, Oral; Aged; Aged, 80 and over; Ampulla of Vater; Bile Duct Neoplasms; Biliary Tract Neoplasms; DNA-Binding Proteins; Exome Sequencing; Female; Gallbladder Neoplasms; Humans; Male; Middle Aged; Neurofibromin 1; Nuclear Proteins; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Survival Analysis; Transcription Factors; Treatment Outcome

Topics: Antineoplastic Agents; Gallbladder Neoplasms; Humans; Imidazoles; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Middle Aged; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Time Factors; Treatment Outcome

The aim of this study was to profile somatic mutation spectrum in gallbladder cancers (GBCs), and determine the role of MAP kinase pathway in GBC by a series of in vitro and in vivo studies. We performed targeted massively parallel sequencing of DNA isolated from GBCs and matched blood from 14 GBC patients to search for mutations in 504 genes commonly altered in human cancers. We identified recurrent mutations enriched in several major signaling pathways including MAP kinase, Wnt/β-catenin and NF-κB pathways. Immunohistochemistry analysis further validated overactivation of MAP kinase and Wnt pathways in a panel of GBC samples. By treating GBC cells with MEK inhibitor trametinib, we found that trametinib not only dramatically inhibited the activity of MAPK/ERK pathway, but also blocked the Wnt/β-catenin signaling through decreasing β-catenin expression or suppressing nucleus translocation of β-catenin. Moreover, trametinib inhibited the proliferation of GBC cell in a dose- and time-dependent manner, induced GBC cell apoptosis, and inhibited GBC cell migration and invasion. Growth of xenograft tumors derived from GBC cell line NOZ in nude mice was also significantly inhibited by trametinib. Our data highlight the critical role of MAP kinase pathways in GBC pathogenesis, and may represent therapeutic targets for this cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; DNA Mutational Analysis; Gallbladder Neoplasms; High-Throughput Nucleotide Sequencing; Humans; MAP Kinase Signaling System; Mice; Molecular Targeted Therapy; Mutation; NF-kappa B; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; Tumor Stem Cell Assay; Wnt Signaling Pathway; Xenograft Model Antitumor Assays