binimetinib and Disease-Models--Animal

Septic cardiomyopathy (SCM) has a worse prognosis with mortality rates of up to 70%. Most existing treatment is useless and no specific drug or treatment has been found in patients with myocardial hypofunction.. We explored the efficacy of the target drugs (Binimetinib) in SCM model in vivo based on high throughput sequencing and bioinformatics analysis. Firstly, a stable SCM mice model was constructed. Secondly, the hub genes of SCM were clarified by high throughput sequencing and bioinformatics analysis. The related pathways and biological process were revealed by Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology (GO) enrichment analysis. Thirdly, the target drugs of the hub genes were investigated by network pharmacology analysis. Fourthly, the curative effects and hub genes regulatory effects of Binimetinib were demonstrated by SCM mice model. Finally, the regulatory mechanism of the target drugs on the hub genes were analyzed by molecular docking.. A stable SCM model was established by wound P. aeruginosa infection. Tnf, Il-1β, Il-6 were the key genes of SCM. Binimetinib might be a drug for the treatment of SCM by downregulating the hub genes. Its active mechanism might be related to NFKB1.

Topics: Animals; Benzimidazoles; Cardiomyopathies; Disease Models, Animal; Interleukin-6; Mice; Molecular Docking Simulation

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Advanced ovarian cancer is very responsive to first line platinum therapy, however almost invariably it relapses with a resistant disease. We have reported that patient derived ovarian xenografts (PDXs), independently from the degree of the initial response to cisplatin (DDP), show a significantly lower response to a second DDP cycle. We here report the effect of new combination regimens containing a MEK inhibitor (MEK), bevacizumab (BEV) and paclitaxel (PTX) as second line therapy in platinum-relapsing PDXs.We selected three DDP-relapsing PDX models based on the presence of activation of the RAS/RAF/MEK/ERK axis, mutated p53, lack of PTEN expression and activation of the PI3K pathway. In all the selected xenograft models, the antitumor efficacy of the doublets can be summarized as PTX/BEV > BEV/MEK > PTX/MEK and the antitumor activity of the triple combination was higher than any double combination. All the different combinations were well tolerated. The present data corroborate the activity of bevacizumab in combination with chemotherapy for the treatment of relapsing ovarian tumors and suggest that the addition of another targeted agents (MEK inhibitor) can further increase the antitumor activity without any increase in toxicity. PDX models represent a useful model to test second line therapy after failure of DDP first line.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bevacizumab; Biomarkers; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Humans; Mice; Mutation; Ovarian Neoplasms; Paclitaxel; Platinum; Recurrence; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Involuntary weight loss, a part of the cachexia syndrome, is a debilitating comorbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEK inhibition might be anticachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK1/2 inhibitor MEK162. Results showed that MEK inhibition effectively prevented muscle wasting. Importantly, MEK162 retained its ability to spare muscle loss even in mice bearing a Colon-26 clone resistant to the MEK inhibitor, demonstrating that the effects of blocking MEK are at least in part independent of the tumor. Because single-agent MEK inhibitors have been limited as a first-line targeted therapy due to compensatory activation of other oncogenic signaling pathways, we combined MEK162 with the PI3K/Akt inhibitor buparlisib. Results showed that this combinatorial treatment significantly reduced tumor growth due to a direct activity on Colon-26 tumor cells in vitro and in vivo, while also preserving skeletal muscle mass. Together, our results suggest that as a monotherapy, MEK inhibition preserves muscle mass, but when combined with a PI3K/Akt inhibitor exhibits potent antitumor activity. Thus, combinatorial therapy might serve as a new approach for the treatment of cancer cachexia. Mol Cancer Ther; 16(2); 344-56. ©2016 AACRSee related article by Kobayashi et al., p. 357.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Benzimidazoles; Biomarkers; Body Weight; Cachexia; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Morpholines; Muscle, Skeletal; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Xenograft Model Antitumor Assays

The objective of tailoring medicines for cancer patients according to the molecular profile of their disease holds great promise for the improvement of cancer therapy. Nevertheless, this approach has been limited, in part, due to the lack of predictive and informative preclinical studies. Herein, we describe an assessment of the therapeutic potential of targeting PI3K/mTOR and MAPK signaling in genetically defined mouse models of colorectal cancer mirroring disease subtypes targeted for novel therapy in the FOCUS4 trial. Our studies demonstrate that dual PI3K/mTOR inhibition is highly effective in invasive adenocarcinoma models characterized by combinatorial mutations in Apc and Pten; Apc and Kras; and Apc, Pten and Kras. MEK inhibition was effective in the combinatorial Apc and Kras setting, but had no impact in either Apc Pten mutants or in Apc Pten Kras triple mutants. Furthermore, we describe the importance of scheduling for combination studies and show that although no additional benefit is gained in Apc Pten mice, combination of PI3K/mTOR and MAPK inhibition leads to an additive benefit in survival in Apc Kras mice and a synergistic increase in survival in Apc Pten Kras mice. This is the first study using robust colorectal cancer genetically engineered mouse models to support the validity of PI3K/mTOR and MEK inhibitors as tailored therapies for colorectal cancer and highlight the potential importance of drug scheduling in the clinic.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Benzimidazoles; Colorectal Neoplasms; Disease Models, Animal; Drug Screening Assays, Antitumor; Genes, APC; Imidazoles; MAP Kinase Kinase Kinases; Mice, Transgenic; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; Quinolines; Tumor Burden