crizotinib and Adenocarcinoma--Clear-Cell

Salivary gland secretory carcinoma is usually a low-grade neoplasm. However, high-grade transformation can occur and has important implications for clinical outcome.. A patient presented with an enlarging buccal mass. Magnetic resonance imaging (MRI) showed a tumor with a biphasic appearance along the right parotid duct. Local excision and histopathologic examination confirmed the diagnosis of secretory carcinoma with high-grade transformation. ETV6-NTRK3 translocation and loss of CDKN2A/B were identified.. The patient subsequently presented with cough and dyspnea and was found to have pleural metastases. Carboplatin and paclitaxel exacerbated the symptoms. Crizotinib resulted in initial symptomatic and radiographic improvement; however, the patient soon succumbed to progressive intrathoracic disease.. High-grade salivary gland secretory carcinoma can have a biphasic appearance on MRI. Diagnosis is confirmed by the histologic appearance and associated ETV6-NTRK3 fusion. Additional molecular genetic events leading to transformation are unknown; however, loss of CDKN2A/B may have contributed. Treatment with multimodal chemotherapy was of limited benefit.

Topics: Adenocarcinoma, Clear Cell; Adult; Antineoplastic Combined Chemotherapy Protocols; Crizotinib; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p18; Diagnosis, Differential; Disease Progression; Drug Resistance, Neoplasm; Fatal Outcome; Gene Rearrangement; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Male; Mammary Analogue Secretory Carcinoma; Myoepithelioma; Oncogene Proteins, Fusion; Parotid Gland; Pleural Neoplasms; Pyrazoles; Pyridines; Salivary Gland Neoplasms; Translocation, Genetic; Treatment Outcome

In this study, we investigated the therapeutic effects of c-MET inhibition in ovarian clear cell carcinoma (OCCC). Expression levels of c-MET in the epithelial ovarian cancers (EOCs) and normal ovarian tissues were evaluated using real-time PCR. To test the effects of c-MET inhibitors in OCCC cell lines, we performed MTT and apoptosis assays. We used Western blots to evaluate the expression of c-MET and its down-stream pathway. In vivo experiments were performed to test the effects of c-MET inhibitor on tumor growth in orthotopic mouse xenografts of OCCC cell line RMG1 and a patient-derived tumor xenograft (PDX) model of OCCC. c-MET expression was significantly greater in OCCCs compared with serous carcinomas and normal ovarian tissues (p < 0.001). In in vitro study, inhibition of c-MET using c-MET inhibitors (SU11274 or crizotinib) significantly decreased the proliferation, and increased the apoptosis of OCCC cells. SU11274 decreased expression of the p-c-MET proteins and blocked the phosphorylation of down-stream proteins Akt and Erk. Furthermore, SU11274 treatment significantly decreased the in vivo tumor weight in xenograft models of RMG1 cell and a PDX model for OCCC compared to control (p = 0.004 and p = 0.009, respectively).

Topics: Adenocarcinoma, Clear Cell; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Crizotinib; Female; Gene Expression Regulation, Neoplastic; Humans; Indoles; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Neoplasm Proteins; Ovarian Neoplasms; Phosphorylation; Piperazines; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Signal Transduction; Sulfonamides; Xenograft Model Antitumor Assays