pyrimidinones and Mesothelioma

Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy.. This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed.. Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks).. Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD.

Topics: Aged; Aminopyridines; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Focal Adhesion Protein-Tyrosine Kinases; Humans; Hydroxamic Acids; Male; Mesothelioma; Middle Aged; Neoplasms; Progression-Free Survival; Pyridones; Pyrimidinones

Merlin is encoded by Neurofibromatosis type 2 gene (NF-2), a tumor suppressor gene, which causes some multiple tumors forming disease of the nervous system in case of function loss. Bioinformatics analysis suggested that patients with NF-2 mutation had a worse prognosis, while it was associated with PI3K/mTOR activation, implying abnormal apoptosis in NF-2 mutation related tumors. Hence, we supposed that the inhibitors of PI3K/mTOR pathway might play a role in suppressing the tumor proliferation.. Two representative NF-2 mutation tumor model of NCI-H2452 and HEI193 cell lines were adopted, while two PI3K/mTOR pathway inhibitors Trametinib and Vistusertib were chosen to study the proliferation and apoptosis of the tumor cells.. CCK8 cell counting experiment showed that both Trametinib and Vistusertib could inhibit the proliferation of NCI-H2452 cell in vitro, while the combination of Trametinib and Vistusertib was more significant. Flow cytometry results showed that both Trametinib and Vistusertib could enhance apoptosis of NCI-H2452 cell in vitro, while the combination of Trametinib and Vistusertib was more significant. Similar results were also achieved for HEI193 cell lines. In vivo tumorigenicity experiments demonstrated that the tumor volume and weight were significantly decreased by both Trametinib and Vistusertib, while their combination had the most significant effect. Western blot results demonstrated that both Trametinib and Vistusertib could inhibit PI3K/mTOR /MEK pathway and enhance the expression of merlin.. We found that PI3K/mTOR inhibitor could decrease the proliferation of NF-2 mutation tumor cell lines by enhancing apoptosis, while the combination of two drugs might have a better effect.

Topics: Antineoplastic Agents; Apoptosis; Benzamides; Cell Proliferation; Cells, Cultured; Computational Biology; Drug Screening Assays, Antitumor; Humans; Mesothelioma; Morpholines; Mutation; Neurofibromin 2; Phosphatidylinositol 3-Kinase; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Pyrimidinones; TOR Serine-Threonine Kinases

Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy in which the mitogen-activated protein kinase pathway plays a critical role in the regulation of tumorigenesis. Hyaluronic acid (HA) is a major component of the extracellular matrix, and elevated HA levels with a concurrent increase in malignant properties are associated with MPM.. We evaluated the effects of trametinib, a mitogen-activated protein kinase (MEK) inhibitor, and 4-methylumbelliferone (4-MU), an HA synthesis inhibitor, alone and in combination on MPM cells in vitro and in vivo. We studied the effects of trametinib, 4-MU, and their combination on MPM cells by using cell viability assays, Western blot analysis, and a mouse xenograft model.. Trametinib and 4-MU exhibited antiproliferative activity in MPM cells. Trametinib blocked MEK-dependent extracellular signal-regulated kinase (ERK) phosphorylation and decreased CD44 expression in a concentration-dependent manner. Trametinib inhibited the expression of Fra-1 (the activator protein 1 [AP1] component), inhibited ERK phosphorylation, and decreased CD44 expression. 4-MU inhibited ERK phosphorylation but not CD44 expression. In a mouse xenograft model, trametinib and 4-MU alone suppressed tumor growth compared with a control. The combination had a greater inhibitory effect than either monotherapy. Immunohistochemical analysis showed that trametinib treatment alone significantly reduced expression of programmed cell death 1 ligand 1. Furthermore, the combination of trametinib and 4-MU resulted in higher expression of programmed cell death 1 and programmed cell death 1 ligand 1 than did the 4-MU treatment alone.. Our results suggest that trametinib and 4-MU are promising therapeutic agents in MPM and that further study of the combination is warranted.

Topics: Animals; Antineoplastic Agents; Apoptosis; B7-H1 Antigen; Cell Proliferation; Drug Therapy, Combination; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors; Hymecromone; Indicators and Reagents; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Mice, Inbred BALB C; Mice, Nude; Pleural Neoplasms; Programmed Cell Death 1 Receptor; Pyridones; Pyrimidinones; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Malignant mesothelioma (MM) is a very aggressive asbestos-related neoplasm of the serous membranes, whose incidence is increasing worldwide. Although the introduction of new drug combinations, such as cisplatin plus pemetrexed/gemcitabine, has determined an improvement in the patient quality of life, MM remains a universally fatal disease. The observation that key G 1/S checkpoint regulators are often functionally inactivated in MM prompted us to test whether the use of G 2/M checkpoint inhibitors, able to sensitize G 1/S checkpoint-defective cancer cells to DNA-damaging agents, could be successful in MM. We treated six MM cell lines, representative of different histotypes (epithelioid, biphasic, and sarcomatoid), with cisplatin in combination with MK-1775, an inhibitor of the G 2/M checkpoint kinase WEE1. We observed that MK-1775 enhanced the cisplatin cytotoxic effect in all MM cell lines, except the sarcomatoid cell line, which is representative of the most aggressive histotype. As expected, the enhancement in cisplatin toxicity was accompanied by a decrease in the inactive phosphorylated form of cyclin-dependent kinase 1 (CDK1), a key substrate of WEE1, which is indicative of G 2/M checkpoint inactivation. Consistently, we also observed a decrease in G 2/M accumulation and an increase in mitotic entry of DNA-damaged cells and apoptosis, probably due to the loss of the cell ability to arrest cell cycle in response to DNA damage, irrespectively of p53 mutational status. Notably, this treatment did not increase cisplatin cytotoxicity on normal cells, thus suggesting a possible use of MK-1775 in combination with cisplatin for a safe and efficient treatment of epithelioid and biphasic MM.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Cisplatin; Drug Synergism; G2 Phase Cell Cycle Checkpoints; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Nuclear Proteins; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones

It has been known for many years that manipulation of cell cycle checkpoint function represents one approach by which the toxicity of chemotherapy and of ionizing radiation can be increased in tumor cells. (1)(-) (3) In particular, abrogation of the G 2/M checkpoint has been shown to enhance the lethality of a wide range of toxic stresses. (1)(-) (3) Inhibition of the G 2/M checkpoint after chemotherapy/irradiation would result in tumor cells entering mitosis with damaged DNA, which would in turn result in loss of clonogenic survival (i.e., a lethal mitosis).

Topics: Antineoplastic Agents; Cell Cycle Proteins; Cisplatin; G2 Phase Cell Cycle Checkpoints; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Nuclear Proteins; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones