pf-3084014 and Neoplasm-Metastasis

pf-3084014 has been researched along with Neoplasm-Metastasis* in 4 studies

Other Studies

4 other study(ies) available for pf-3084014 and Neoplasm-Metastasis

ArticleYear
Identification of FOXN4 as a tumor suppressor of breast carcinogenesis via the activation of TP53 and deactivation of Notch signaling.
    Gene, 2020, 01-05, Volume: 722

    Fork head domain-containing transcription factor family (FOX), is comprised of >20 members. Members of FOX family have been implicated in a wide range of physiological and/or diseased conditions. Many of FOX members have been shown to be involved in tumorigenesis and progression. The potential roles in carcinogenesis of FOXN4, a member as one of the vast FOX family, remains relatively unknown.. Here, we explored the potential involvement of FOXN4 in breast cancer.. First, observed that a higher FOXN4 was identified in the normal adjacent breast tissue as compared to that in the breast cancer samples; an increased FOXN4 level was associated with a better prognosis in patients with breast cancer. In addition, ectopically expression of FOXN4 led to the decreased cell proliferation, reduced colony formation and metastatic abilities (EMT, migration and invasion) in breast cancer cell lines. Furthermore, we showed the direct interaction between FOXN4 and TP53 and FOXN4 binding led to the increased activity of TP53. Silencing FOXN4 led to reduced TP53 and increased expression of Dll4, Notch and survivin, providing a link between FOXN4 and Notch signaling. Finally, we used patient-derived xenograft mouse model to demonstrate the tumor inhibitory effects of Notch-inhibitor, PF-3084014. We found that PF-3084014 treatment led to a significantly smaller tumor burden and higher survival ratio in patient-derived xenograft mice as compared to the vehicle. This tumor suppressive effect was accompanied by the increased expression of TP53, FOXN4 and decreased Dll4 and Notch.. Collectively, our data strongly suggested the tumor suppressive roles of FOXN4 in breast tumorigenesis via the activation of TP53 while suppressing Notch signaling. Future studies are warranted to explore the clinical application of PF-3084104 (Notch inhibitor) for the treatment of breast cancer patients.

    Topics: Adaptor Proteins, Signal Transducing; Adult; Animals; Breast Neoplasms; Calcium-Binding Proteins; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Female; Forkhead Transcription Factors; Humans; Intercellular Signaling Peptides and Proteins; Mammary Neoplasms, Experimental; Mice; Neoplasm Metastasis; Prognosis; Receptors, Notch; Signal Transduction; Tetrahydronaphthalenes; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Valine

2020
Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1-Stat3.
    Molecular cancer therapeutics, 2017, Volume: 16, Issue:8

    Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma, indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (γ-secretase inhibitor) PF-03084014 in hepatocellular carcinoma. Hepatocellular carcinoma spherical cells (stem-like cancer cells), a sphere-derived orthotopic tumor model and one patient-derived xenograft (PDX) model were used in our experiment. We demonstrated that PF-03084014 inhibited the self-renewal and proliferation of cancer stem cells. PF-03084014 reduced the hepatocellular carcinoma sphere-derived orthotopic tumor and blocked the hepatocellular carcinoma tumor liver to lung metastasis. We further tested the PF-03084014 in PDX models and confirmed the inhibition tumor growth effect. In addition, a low dose of PF-03084014 induced hepatocellular carcinoma sphere differentiation, resulting in chemosensitization. Antitumor activity was associated with PF-03084014-induced suppression of Notch1 activity, decreased Stat3 activation and phosphorylation of the Akt signaling pathway, and reduced epithelial-mesenchymal transition. These are the key contributors to the maintenance of cancer stemness and the promotion of cancer metastasis. Moreover, the Notch-Stat3 association was implicated in the clinical hepatocellular carcinoma prognosis. Collectively, PF-03084014 revealed antitumor and antimetastatic effects in hepatocellular carcinoma, providing evidence for the potential use of gamma-secretase inhibitors as a therapeutic option for the treatment of hepatocellular carcinoma.

    Topics: Antineoplastic Agents; Carcinogenesis; Carcinoma, Hepatocellular; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Self Renewal; Humans; Liver Neoplasms; Neoplasm Metastasis; Neoplastic Stem Cells; Receptor, Notch1; Spheroids, Cellular; STAT3 Transcription Factor; Tetrahydronaphthalenes; Valine

2017
The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.
    Leukemia, 2015, Volume: 29, Issue:1

    Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), especially for the poor prognostic subgroup of NOTCH1-mutated patients. Here, we report that the γ-secretase inhibitor PF-03084014 inhibits the constitutive Notch activation and induces selective apoptosis in CLL cells carrying NOTCH1 mutations. Combination of PF-03084014 with fludarabine has a synergistic antileukemic effect in primary NOTCH1-mutated CLL cells, even in the presence of the protective stroma. At transcriptional level, PF-03084014 plus fludarabine treatment induces the upregulation of the proapoptotic gene HRK and the downmodulation of MMP9, IL32 and RAC2 genes that are related to invasion and chemotaxis. PF-03084014 also overcomes fludarabine-mediated activation of nuclear factor-κB signaling. Moreover, this combination impairs angiogenesis and CXCL12-induced responses in NOTCH1-mutated CLL cells, in particular those related to tumoral migration and invasion. Importantly, all these collaborative effects are specific for NOTCH1 mutation and do not occur in unmutated cases. In conclusion, we provide evidence that Notch is a therapeutic target in CLL cases with NOTCH1-activating mutations, supporting the use of Notch pathway inhibitors in combination with chemotherapy as a promising approach for the treatment of these high-risk CLL patients.

    Topics: Aged; Amyloid Precursor Protein Secretases; Enzyme Inhibitors; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Receptor, Notch1; Tetrahydronaphthalenes; Tumor Cells, Cultured; Valine; Vidarabine

2015
Biomarker and pharmacologic evaluation of the γ-secretase inhibitor PF-03084014 in breast cancer models.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2012, Sep-15, Volume: 18, Issue:18

    We aimed to assess the biologic activity of PF-03084014 in breast xenograft models. The biomarkers for mechanism and patient stratification were also explored.. The in vitro and in vivo properties of PF-03084014 were investigated. The mRNA expressions of 40 key Notch pathway genes at baseline or after treatment were analyzed to link with the antitumor efficacy of PF-03084014 in a panel of breast cancer xenograft models.. In vitro, PF-03084014 exhibited activity against tumor cell migration, endothelial cell tube formation, and mammosphere formation. In vivo, we observed apoptosis, antiproliferation, reduced tumor cell self-renewal ability, impaired tumor vasculature, and decreased metastasis activity after the treatment of PF-03084014. PF-03084014 treatment displayed significant antitumor activity in 10 of the 18 breast xenograft models. However, the antitumor efficacy in most models did not correlate with the in vitro antiproliferation results in the corresponding cell lines, suggesting the critical involvement of tumor microenvironment during Notch activation. In the tested breast xenograft models, the baseline expressions of the Notch receptors, ligands, and the cleaved Notch1 failed to predict the antitumor response to PF-03084014, whereas several Notch pathway target genes, including HEY2, HES4, and HES3, strongly corresponded with the response with a P value less than 0.01. Many of the best molecular predictors of response were also significantly modulated following PF-03084014 treatment.. PF-03084014 showed antitumor and antimetastatic properties via pleiotropic mechanisms. The Notch pathway downstream genes may be used to predict the antitumor activity of PF-03084014 and enrich for responders among breast cancer patients.

    Topics: Amyloid Precursor Protein Secretases; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Cluster Analysis; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Neoplasm Metastasis; Receptors, Notch; Signal Transduction; Tetrahydronaphthalenes; Valine; Xenograft Model Antitumor Assays

2012
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