pyrimidinones and Kidney-Neoplasms

WEE1 is a serine kinase central to the G. AZD1775 was tested using a dose of 120 mg/kg administered orally for days 1 to 5. Irinotecan was administered intraperitoneally at a dose of 2.5 mg/kg for days 1 to 5 (one hour after AZD1775 when used in combination). AZD1775 and irinotecan were studied alone and in combination in neuroblastoma (n = 3), osteosarcoma (n = 4), and Wilms tumor (n = 3) xenografts.. AZD1775 as a single agent showed little activity. Irinotecan induced objective responses in two neuroblastoma lines (PRs), and two Wilms tumor models (CR and PR). The combination of AZD1775 + irinotecan-induced objective responses in two neuroblastoma lines (PR and CR) and all three Wilms tumor lines (CR and 2 PRs). The objective response measure improved compared with single-agent treatment for one neuroblastoma (PR to CR), two osteosarcoma (PD1 to PD2), and one Wilms tumor (PD2 to PR) xenograft lines. Of note, the combination yielded CR (n = 1) and PR (n = 2) in all the Wilms tumor lines. The event-free survival was significantly longer for the combination compared with single-agent irinotecan in all models tested. The magnitude of the increase was greatest in osteosarcoma and Wilms tumor xenografts.. AZD1775 potentiates the effects of irinotecan across most of the xenograft lines tested, with effect size appearing to vary across tumor panels.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Child; Female; Humans; Irinotecan; Kidney Neoplasms; Mice; Mice, SCID; Neoplasms, Experimental; Neuroblastoma; Pyrazoles; Pyrimidinones; Wilms Tumor; Xenograft Model Antitumor Assays

Current treatments for clear cell renal cell cancer (ccRCC) are insufficient because two-thirds of patients with metastases progress within two years. Here we report the identification and characterization of a cancer stem cell (CSC) population in ccRCC. CSCs are quantitatively correlated with tumor aggressiveness and metastasis. Transcriptional profiling and single cell sequencing reveal that these CSCs exhibit an activation of WNT and NOTCH signaling. A significant obstacle to the development of rational treatments has been the discrepancy between model systems and the in vivo situation of patients. To address this, we use CSCs to establish non-adherent sphere cultures, 3D tumor organoids, and xenografts. Treatment with WNT and NOTCH inhibitors blocks the proliferation and self-renewal of CSCs in sphere cultures and organoids, and impairs tumor growth in patient-derived xenografts in mice. These findings suggest that our approach is a promising route towards the development of personalized treatments for individual patients.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Female; Heterocyclic Compounds, 3-Ring; Humans; Kidney; Kidney Neoplasms; Male; Mice; Middle Aged; Neoplastic Stem Cells; Primary Cell Culture; Pyrimidinones; Receptors, Notch; RNA, Small Interfering; Signal Transduction; Single-Cell Analysis; Spheroids, Cellular; Wnt Proteins; Xenograft Model Antitumor Assays

Speckle-type POZ protein (SPOP) is overexpressed in the nucleus and misallocated in the cytoplasm in almost all the clear-cell renal cell carcinomas (ccRCCs), which leads to kidney tumorigenesis. Previously, we elucidated that the oncogenic SPOP-signaling pathway in ccRCC could be suppressed by

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; HEK293 Cells; Humans; Kidney Neoplasms; Molecular Structure; Nuclear Proteins; Protein Binding; PTEN Phosphohydrolase; Pyridines; Pyrimidinones; Repressor Proteins; Structure-Activity Relationship

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

Donor-derived malignancy, particularly melanoma, is a rare but known complication of organ transplantation. Here we describe a case of metastatic melanoma in a deceased-donor kidney transplant recipient. After diagnosis, the patient was successfully treated with cessation of immunosuppression, explantation of the renal allograft, and novel melanoma therapies, including the mutation-targeted agents dabrafenib and trametinib and the immune checkpoint inhibitor nivolumab. These 2 new classes of melanoma therapy have revolutionized the course of metastatic melanoma, altering it from one of nearly certain mortality to one of potential cure. This case reviews the mechanisms of action of these therapies and reports our experience with them in the rare setting of donor-derived melanoma in a dialysis-dependent patient.

Topics: Allografts; Antibodies, Monoclonal; Antineoplastic Agents; Checkpoint Kinase 1; Checkpoint Kinase 2; Humans; Imidazoles; Kidney; Kidney Neoplasms; Kidney Transplantation; Liver Neoplasms; Lung Neoplasms; Male; Melanoma; Middle Aged; Nivolumab; Oximes; Pyridones; Pyrimidinones; Tissue Donors

Sunitinib and pazopanib are antiangiogenic tyrosine kinase inhibitors (TKI) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors that are resistant to sunitinib have a significantly increased angiogenic response compared with tumors that are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared with sensitive tumors. These data suggested that the Ras-Raf-MEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI-resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent antiangiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppression of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Drug Synergism; Endothelial Cells; Female; Humans; Indoles; Kidney Neoplasms; MAP Kinase Signaling System; Neovascularization, Pathologic; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Pyrroles; Sunitinib; Von Hippel-Lindau Tumor Suppressor Protein; Xenograft Model Antitumor Assays

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

c-Met is a receptor tyrosine kinase often deregulated in human cancers, thus making it an attractive drug target. One mechanism by which c-Met deregulation leads to cancer is through gain-of-function mutations. Therefore, small molecules capable of targeting these mutations could offer therapeutic benefits for affected patients. SU11274 was recently described and reported to inhibit the activity of the wild-type and some mutant forms of c-Met, whereas other mutants are resistant to inhibition. We identified a novel series of c-Met small molecule inhibitors that are active against multiple mutants previously identified in hereditary papillary renal cell carcinoma patients. AM7 is active against wild-type c-Met as well as several mutants, inhibits c-Met-mediated signaling in MKN-45 and U-87 MG cells, and inhibits tumor growth in these two models grown as xenografts. The crystal structures of AM7 and SU11274 bound to unphosphorylated c-Met have been determined. The AM7 structure reveals a novel binding mode compared with other published c-Met inhibitors and SU11274. The molecule binds the kinase linker and then extends into a new hydrophobic binding site. This binding site is created by a significant movement of the C-helix and so represents an inactive conformation of the c-Met kinase. Thus, our results demonstrate that it is possible to identify and design inhibitors that will likely be active against mutants found in different cancers.

Topics: Animals; Binding Sites; Carcinoma, Renal Cell; Cell Line, Tumor; Crystallography, X-Ray; Drug Design; Female; Humans; Indoles; Kidney Neoplasms; Mice; Mice, Nude; Models, Molecular; Mutation; Neoplasm Transplantation; Piperazines; Protein Conformation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrimidinones; Quinolines; Recombinant Fusion Proteins; Sulfonamides; Transplantation, Heterologous