tgx-221 and Kidney-Neoplasms
tgx-221 has been researched along with Kidney-Neoplasms* in 2 studies
Other Studies
2 other study(ies) available for tgx-221 and Kidney-Neoplasms
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Inactivation of endothelial cell phosphoinositide 3-kinase β inhibits tumor angiogenesis and tumor growth.
Angiogenesis inhibitors, such as the receptor tyrosine kinase (RTK) inhibitor sunitinib, target vascular endothelial growth factor (VEGF) signaling in cancers. However, only a fraction of patients respond, and most ultimately develop resistance to current angiogenesis inhibitor therapies. Activity of alternative pro-angiogenic growth factors, acting via RTK or G-protein coupled receptors (GPCR), may mediate VEGF inhibitor resistance. The phosphoinositide 3-kinase (PI3K)β isoform is uniquely coupled to both RTK and GPCRs. We investigated the role of endothelial cell (EC) PI3Kβ in tumor angiogenesis. Pro-angiogenic GPCR ligands were expressed by patient-derived renal cell carcinomas (PD-RCC), and selective inactivation of PI3Kβ reduced PD-RCC-stimulated EC spheroid sprouting. EC-specific PI3Kβ knockout (ΕC-βKO) in mice potentiated the sunitinib-induced reduction in subcutaneous growth of LLC1 and B16F10, and lung metastasis of B16F10 tumors. Compared to single-agent sunitinib treatment, tumors in sunitinib-treated ΕC-βKO mice showed a marked decrease in microvessel density, and reduced new vessel formation. The fraction of perfused mature tumor microvessels was increased in ΕC-βKO mice suggesting immature microvessels were most sensitive to combined sunitinib and PI3Kβ inactivation. Taken together, EC PI3Kβ inactivation with sunitinib inhibition reduces microvessel turnover and decreases heterogeneity of the tumor microenvironment, hence PI3Kβ inhibition may be a useful adjuvant antiangiogenesis therapy with sunitinib. Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Kidney Neoplasms; Melanoma, Experimental; Mice, Knockout; Microvessels; Morpholines; Neovascularization, Pathologic; Protein Kinase Inhibitors; Pyrimidinones; Sunitinib; Thiazoles; Tumor Microenvironment; Vascular Endothelial Growth Factor Receptor-2 | 2020 |
PI3Kβ inhibitor TGX221 selectively inhibits renal cell carcinoma cells with both VHL and SETD2 mutations and links multiple pathways.
We aimed to exploit novel compounds with high selectivity to clear cell renal cell carcinoma (ccRCC) with common mutations. Using the GDSC databases, we searched for compounds with high selectivity for ccRCC with VHL and/or SETD2 mutations. Clinical impact and gene interactions were analysed using TCGA database. In vitro and in vivo studies were performed to validate the inhibitory effects of the compound. We identified the selective PI3Kβ inhibitor TGX221 as a selective inhibitor for ccRCC with both VHL and SETD2 mutations. TGX221 also targeted cancer cells with CDKN2A and PTEN mutations. Changes in PTEN and CDKN2A gene sets were associated with worsened prognosis of ccRCC. TGX221 substantially and selectively inhibited the down stream products of VHL, SETD2, and PTEN in ccRCC cells with VHL and SETD2 mutations. TGX221 also exhibited significant selectivity in inhibiting cell motility and tumourigenesis of ccRCC cells with VHL and SETD2 mutations. TGX221 is a novel inhibitor with high selectivity for ccRCC with VHL and SETD2 mutations. It also targeted PTEN and CDKN2A mutations. How those genes were associated with PI3Kβ warranted further investigations. Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Cyclin-Dependent Kinase Inhibitor p16; Drug Resistance, Neoplasm; Histone-Lysine N-Methyltransferase; Humans; Kidney Neoplasms; Morpholines; Mutation; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; PTEN Phosphohydrolase; Pyrimidinones; Receptor, Notch1; Signal Transduction; Von Hippel-Lindau Tumor Suppressor Protein | 2015 |