pyrimidinones and Neoplasms--Germ-Cell-and-Embryonal

The majority of patients with testicular germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. However, for a subset of patients present with cisplatin-refractory disease, which confers a poor prognosis, the treatment options are limited. Novel therapies are therefore urgently needed to improve outcomes in this challenging patient population. It has previously been shown that Wnt/β-catenin signaling is active in GCTs suggesting that its inhibitors LGK974 and PRI-724 may show promise in the management of cisplatin-refractory GCTs. We herein investigated whether LGK-974 and PRI-724 provide a treatment effect in cisplatin-resistant GCT cell lines. Taking a genoproteomic approach and utilizing xenograft models we found the increased level of β-catenin in 2 of 4 cisplatin-resistant (CisR) cell lines (TCam-2 CisR and NCCIT CisR) and the decreased level of β-catenin and cyclin D1 in cisplatin-resistant NTERA-2 CisR cell line. While the effect of treatment with LGK974 was limited or none, the NTERA-2 CisR exhibited the increased sensitivity to PRI-724 in comparison with parental cell line. Furthermore, the pro-apoptotic effect of PRI-724 was documented in all cell lines. Our data strongly suggests that a Wnt/β-catenin signaling is altered in cisplatin-resistant GCT cell lines and the inhibition with PRI-724 is effective in NTERA-2 CisR cells. Further evaluation of Wnt/β-catenin pathway inhibition in GCTs is therefore warranted.

Topics: Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Humans; Immunohistochemistry; Male; Mice; Mice, SCID; Neoplasms, Germ Cell and Embryonal; Pyrazines; Pyridines; Pyrimidinones; Testicular Neoplasms; Wnt Signaling Pathway

Hematologic malignancies arising in the setting of established germ cell tumors have been previously described and have a dismal prognosis. Identification of targetable mutations and pathway dysregulation through massively parallel sequencing and functional assays provides new approaches to disease management.. Herein, we report the case of a 23-year-old male who was diagnosed with a mediastinal germ cell tumor and subsequent acute myeloid leukemia. A shared clonal origin was demonstrated through identification of identical NRAS and TP53 somatic mutations in both malignancies. The patient's leukemia was refractory to standard therapies with short interval relapse. Functional assays demonstrated the patient's blasts to be sensitive to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, correlating with the activating NRAS mutation. The patient experienced a sustained partial remission while on trametinib therapy but ultimately suffered relapse of the germ cell tumor. The leukemic clone remained stable and sensitive to trametinib at that time.. This case highlights the potential power of combining genetic sequencing and in vitro functional assays with targeted therapies in the treatment of rare diseases.

Topics: Acute Disease; GTP Phosphohydrolases; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myeloid; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mediastinal Neoplasms; Membrane Proteins; Neoplasm Recurrence, Local; Neoplasms, Germ Cell and Embryonal; Point Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Treatment Outcome; Tumor Suppressor Protein p53; Young Adult