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OBJECTIVES: The immune cell infiltration (ICI) in the tumor microenvironment (TME) can provide a reference for prognosis after immunotherapy. We aim to establish an ICI scoring model and evaluate its predictive ability for the immunotherapy efficacy and the prognosis in lung adenocarcinoma (LUAD) patients. METHODS: We developed and analyzed the landscape of infiltrative immune cells based on the CIBERSORT and ESTIMATE algorithms. Then, three clusters of LUAD patients were discerned from TCGA-LUAD and GSE11969 data. Furthermore, two gene clusters were classified based on the PCA. RESULTS: LUAD patients with better prognoses tend to have higher immune checkpoint expression and immune/stromal scores. There is a correlation between TMB and ICI, and their relationship deserves further exploration. Moreover, the early-stage and male patients with high ICI scores have more prolonged survival. CONCLUSIONS: The feasibility of the ICI score model in evaluating prognosis after immune checkpoint therapy for LUAD patients was verified, specifically reflected in the screening of sensitive immune checkpoints as a treatment reference. The scoring system can accurately predict the overall survival of LUAD patients, which has clinical value to monitor disease and evaluate prognosis.
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A series of pyrimidodiazepines was identified as potent Polo-like kinase 1 (PLK1) inhibitors. The synthesis and SAR are discussed. The lead compound 7 (RO3280) has potent inhibitory activity against PLK1, good selectivity against other kinases, and excellent in vitro cellular potency. It showed strong antitumor activity in xenograft mouse models.
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Antineoplásicos/farmacologia , Azepinas/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Azepinas/síntese química , Azepinas/química , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Estereoisomerismo , Relação Estrutura-Atividade , Quinase 1 Polo-LikeRESUMO
Savolitinib is a novel small-molecule selective cMet inhibitor. This work characterized its pharmacokinetics in preclinical phase, established the preclinical relationships between PK, cMet modulation and anti-tumor efficacy. In vitro and in vivo animal studies were performed for PK characterization. Savolitinib showed good absorption, moderate tissue distribution, low to intermediate clearance, and low accumulation. Hepatic oxidative metabolism followed by urinary and biliary excretions was the major elimination pathway. Based on preclinical PK data, human PK profiles were predicted using empirical methods. Pharmacodynamic studies for evaluating cMet inhibition and anti-tumor efficacy were conducted in nude mice bearing Hs746t xenograft. PK/PD models were built to link the PD measurements to nude mouse PK. The established integrated preclinical PK/PD model contained a two-compartment non-linear PK model, a biomarker link model and a tumor growth transit model. The IC50 of cMet inhibition and the concentration achieving half of the maximal Hs746t tumor reduction by savolitinib were equal to 12.5 and 3.7â¯nM (free drug), respectively. Based on the predicted human PK data, as well as the established PK/PD model in nude mouse, the human PD (cMet inhibition) profiles were also simulated. This research supported clinical development of savolitinib. Understanding the preclinical PK/PD relationship of savolitinib provides translational insights into the cMet-targeted drug development.
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Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/farmacologia , Pirazinas/farmacocinética , Triazinas/farmacologia , Triazinas/farmacocinética , Animais , Células CACO-2 , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Modelos Biológicos , Proteínas Proto-Oncogênicas c-met/metabolismo , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Targeted therapy is not yet approved for esophageal cancer (EC). In this study, we first evaluated EGFR gene and protein expression in 70 Chinese EC patient tumor samples collected during surgery. We then established 23 patient-derived EC xenograft (PDECX) models and assessed the efficacy of theliatinib, a potent and highly selective EGFR inhibitor currently in Phase I clinical study, in 9 PDECX models exhibiting various EGFR expression levels. Immunohistochemical analysis showed that 50 patient tumor samples (71.4%) had high EGFR expression. Quantitative PCR showed that eight tumors (11.6%) had EGFR gene copy number gain, and fluorescence in situ hybridization (FISH) revealed that four tumors had EGFR gene amplification. These results suggest that EGFR protein may be overexpressed in many EC tumors without gene amplification. Also detected were rare hot-spot mutations in EGFR and PIK3CA, whereas no mutations were found in K-Ras or B-Raf. Theliatinib exhibited strong antitumor activity in PDECX models with high EGFR expression, including remarkable tumor regression in two PDECX models with both EGFR gene amplification and protein overexpression. However, the efficacy of theliatinib was diminished in models with PI3KCA mutations or FGFR1 overexpression in addition to high EGFR expression. This study demonstrates that theliatinib could potentially benefit EC patients with high EGFR protein expression without mutations or aberrant activities of associated factors, such as PI3KCA or FGFR1.
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Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. The receptor tyrosine kinase MET has been implicated as an oncogene in numerous cancer subtypes, including non-small cell lung cancer (NSCLC). Here we explore the therapeutic potential of savolitinib (volitinib, AZD6094, HMPL-504), a potent and selective MET inhibitor, in NSCLC. In vitro, savolitinib inhibits MET phosphorylation with nanomolar potency, which correlates with blockade of PI3K/AKT and MAPK signaling as well as MYC down-regulation. In vivo, savolitinib causes inhibition of these pathways and significantly decreases growth of MET-dependent xenografts. To understand resistance mechanisms, we generated savolitinib resistance in MET-amplified NSCLC cell lines and analyzed individual clones. We found that upregulation of MYC and constitutive mTOR pathway activation is a conserved feature of resistant clones that can be overcome by knockdown of MYC or dual mTORC1/2 inhibition. Lastly, we demonstrate that mechanisms of resistance are heterogeneous, arising via a switch to EGFR dependence or by a requirement for PIM signaling. This work demonstrates the efficacy of savolitinib in NSCLC and characterizes acquired resistance, identifying both known and novel mechanisms that may inform combination strategies in the clinic.
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Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pirazinas/química , Serina-Treonina Quinases TOR/metabolismo , Triazinas/química , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação para Baixo , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-met/metabolismoRESUMO
PURPOSE: To investigate the incidence of cMET gene copy number changes and protein overexpression in Chinese gastric cancer (GC) and to preclinically test the hypothesis that the novel, potent and selective cMET small-molecule inhibitor volitinib, will deliver potent anti-tumor activity in cMET-dysregulated GC patient-derived tumor xenograft (PDX) models. EXPERIMENTAL DESIGN: A range of assays were used and included; in vitro cell line panel screening and pharmacodynamic (PD) analysis, cMET fluorescence in-situ hybridization (FISH) and immunohistochemical (IHC) tissue microarray (TMA) analysis of Chinese GC (n = 170), and anti-tumor efficacy testing and PD analysis of gastric PDX models using volitinib. RESULTS: The incidence of cMET gene amplification and protein overexpression within Chinese patient GC tumors was 6% and 13%, respectively. Volitinib displayed a highly selective profile across a gastric cell line panel, potently inhibiting cell growth only in those lines with dysregulated cMET (EC50 values 0.6 nM/L-12.5 nM/L). Volitinib treatment led to pharmacodynamic modulation of cMET signaling and potent tumor stasis in 3/3 cMET-dysregulated GC PDX models, but had negligible activity in a GC control model. CONCLUSIONS: This study provides an assessment of tumor cMET gene copy number changes and protein overexpression incidence in a cohort of Chinese GC patients. To our knowledge, this is the first study to demonstrate anti-tumor efficacy in a panel of cMET-dysregulated gastric cancer PDX models, using a novel selective cMET-inhibitor (volitinib). Thus, the translational science presented here provides strong rationale for the investigation of volitinib as a therapeutic option for patients with GC tumors harboring amplified cMET.
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Amplificação de Genes , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Triazinas/farmacologia , Animais , Povo Asiático , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-met/biossíntese , Proteínas Proto-Oncogênicas c-met/genética , Transdução de Sinais/genética , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure-activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.
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Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirazinas/farmacologia , Pirazóis/farmacologia , Triazinas/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Ligação Competitiva , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-met/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirazinas/química , Pirazinas/farmacocinética , Pirazóis/química , Pirazóis/farmacocinética , Relação Estrutura-Atividade , Especificidade por Substrato , Triazinas/química , Triazinas/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
VEGF/VEGFR signal axis has been proven to be an important target for development of novel cancer therapies. One challenging aspect in small molecular VEGFR inhibitors is to achieve sustained target inhibition at tolerable doses previously seen only with the long-acting biologics. It would require high potency (low effective drug concentrations) and sufficient drug exposures at tolerated doses so that the drug concentration can be maintained above effective drug concentration for target inhibition within the dosing period. Fruquintinib (HMPL-013) is a small molecule inhibitor with strong potency and high selectivity against VEGFR family currently in Phase II clinical studies. Analysis of Phase I pharmacokinetic data revealed that at the maximum tolerated dose of once daily oral administration fruquintinib achieved complete VEGFR2 suppression (drug concentrations were maintained above that required to produce >85% inhibition of VEGFR2 phosphorylation in mouse) for 24 hours/day. In this article, the preclinical data for fruquintinib will be described, including kinase enzyme activity and selectivity, cellular VEGFR inhibition and VEGFR-driven functional activity, in vivo VEGFR phosphorylation inhibition in the lung tissue in mouse and tumor growth inhibition in a panel of tumor xenograft and patient derive xenograft models in mouse. Pharmacokinetic and target inhibition data are also presented to provide a correlation between target inhibition and tumor growth inhibition.
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Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/administração & dosagem , Benzofuranos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Humanos , Concentração Inibidora 50 , Camundongos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Quinazolinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The p53 tumor suppressor retains its wild-type conformation and transcriptional activity in half of all human tumors, and its activation may offer a therapeutic benefit. However, p53 function could be compromised by defective signaling in the p53 pathway. Using a small-molecule MDM2 antagonist, nutlin-3, to probe downstream p53 signaling we find that the cell-cycle arrest function of the p53 pathway is preserved in multiple tumor-derived cell lines expressing wild-type p53, but many have a reduced ability to undergo p53-dependent apoptosis. Gene array analysis revealed attenuated expression of multiple apoptosis-related genes. Cancer cells with mdm2 gene amplification were most sensitive to nutlin-3 in vitro and in vivo, suggesting that MDM2 overexpression may be the only abnormality in the p53 pathway of these cells. Nutlin-3 also showed good efficacy against tumors with normal MDM2 expression, suggesting that many of the patients with wild-type p53 tumors may benefit from antagonists of the p53-MDM2 interaction.
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Antineoplásicos/farmacologia , Imidazóis/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Inhibition of the prosurvival members of the Bcl-2 family of proteins represents an attractive strategy for the treatment of cancer. We have previously reported the activity of ABT-737, a potent inhibitor of Bcl-2, Bcl-X(L), and Bcl-w, which exhibits monotherapy efficacy in xenograft models of small-cell lung cancer and lymphoma and potentiates the activity of numerous cytotoxic agents. Here we describe the biological activity of A-385358, a small molecule with relative selectivity for binding to Bcl-X(L) versus Bcl-2 (K(i)'s of 0.80 and 67 nmol/L for Bcl-X(L) and Bcl-2, respectively). This compound efficiently enters cells and co-localizes with the mitochondrial membrane. Although A-385358 shows relatively modest single-agent cytotoxic activity against most tumor cell lines, it has an EC(50) of <500 nmol/L in cells dependent on Bcl-X(L) for survival. In addition, A-385358 enhances the in vitro cytotoxic activity of numerous chemotherapeutic agents (paclitaxel, etoposide, cisplatin, and doxorubicin) in several tumor cell lines. In A549 non-small-cell lung cancer cells, A-385358 potentiates the activity of paclitaxel by as much as 25-fold. Importantly, A-385358 also potentiated the activity of paclitaxel in vivo. Significant inhibition of tumor growth was observed when A-385358 was added to maximally tolerated or half maximally tolerated doses of paclitaxel in the A549 xenograft model. In tumors, the combination therapy also resulted in a significant increase in mitotic arrest followed by apoptosis relative to paclitaxel monotherapy.