ABSTRACT
AIM: To evaluate the effect of multidisciplinary treatment (MDT) on the survival outcomes of Chinese lung cancer patients. METHODS: Data from a Chinese tertiary cancer hospital of lung cancer patients were collected and divided into two groups (MDT+/-) according to whether the patients had received an MDT. The survival analysis was performed after propensity score matching (PSM). RESULTS: Before PSM, more patients in the MDT+ group had documented information on clinical characteristics and showed more unfavorable clinical characteristics than patients in the MDT- group. After PSM, there was no imbalance in the first-line treatment strategies between the two groups. When the patients were analyzed separately, for patients in the MDT- group, age at diagnosis, Eastern Cooperative Oncology Group (ECOG) score, stage, smoking history, and epidermal growth factor receptor (EGFR) gene status were all significant factors for survival (p < 0.05). For patients in the MDT+ group, only age at diagnosis, stage, and comorbidities were significant factors for survival (p < 0.05). Moreover, age at diagnosis, ECOG score, stage, EGFR gene status, and MDT were all significant factors for survival for all patients (p < 0.001). The results indicate that MDT was a significant prognostic factor independent of clinical characteristics (HR: 2.095, 95% CI: 1.568-2.800, p < 0.001), with a significantly improved median survival (58.0 vs. 29.0 months, p < 0.001). CONCLUSION: Based on PSM, MDT itself did have a real favorable prognostic significance for Chinese lung cancer patients in the study.
ABSTRACT
BACKGROUND: Regorafenib and other multikinase inhibitors may enhance antitumor efficacy of anti-program cell death-1 (anti-PD1) therapy in hepatocellular carcinoma (HCC). Its immunomodulatory effects, besides anti-angiogenesis, were not clearly defined. METHODS: In vivo antitumor efficacy was tested in multiple syngeneic liver cancer models. Murine bone marrow-derived macrophages (BMDMs) were tested in vitro for modulation of polarization by regorafenib and activation of cocultured T cells. Markers of M1/M2 polarization were measured by quantitative reverse transcription PCR (RT-PCR), arginase activity, flow cytometry, and ELISA. Knockdown of p38 kinase and downstream Creb1/Klf4 signaling on macrophage polarization were confirmed by using knockdown of the upstream MAPK14 kinase, chemical p38 kinase inhibitor, and chromatin immunoprecipitation. RESULTS: Regorafenib (5 mg/kg/day, corresponding to about half of human clinical dosage) inhibited tumor growth and angiogenesis in vivo similarly to DC-101 (anti-VEGFR2 antibody) but produced higher T cell activation and M1 macrophage polarization, increased the ratio of M1/M2 polarized BMDMs and proliferation/activation of cocultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream Creb1/Klf4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells. Synergistic antitumor efficacy between regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment. CONCLUSION: Regorafenib may enhance antitumor immunity through modulation of macrophage polarization, independent of its anti-angiogenic effects. Optimization of regorafenib dosage for rational design of combination therapy regimen may improve the therapeutic index in the clinic.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Cyclic AMP Response Element-Binding Protein/metabolism , Liver Neoplasms/drug therapy , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Tumor-Associated Macrophages/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism , Angiogenesis Inhibitors/pharmacology , Animals , Carcinoma, Hepatocellular/enzymology , Carcinoma, Hepatocellular/immunology , Cell Line, Tumor , Coculture Techniques , Kruppel-Like Factor 4/metabolism , Liver Neoplasms/enzymology , Liver Neoplasms/immunology , Lymphocyte Activation/drug effects , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/enzymology , Lymphocytes, Tumor-Infiltrating/immunology , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Phenotype , Signal Transduction , Tumor Microenvironment , Tumor-Associated Macrophages/enzymology , Tumor-Associated Macrophages/immunologyABSTRACT
PURPOSE: To clarify the effects of cyclin E1 suppression on antitumor efficacy of sorafenib in hepatocellular carcinoma cells and to explore the potential of combining sorafenib with cyclin-dependent kinase (CDK) inhibition in therapy. EXPERIMENTAL DESIGN: The effects of cyclin E1 suppression on sorafenib-induced apoptosis were tested in both sorafenib-sensitive (Huh-7 and HepG2, IC50 5-6 µmol/L) and sorafenib-resistant (Huh-7R and HepG2R, IC50 14-15 µmol/L) hepatocellular carcinoma cells. The activity of pertinent signaling pathways and the expression of cell cycle and apoptosis-related proteins were measured using Western blotting. Efficacy of sorafenib combined with the pan-CDK inhibitor flavopiridol was tested both in vitro and in xenograft experiments. The pertinent downstream mediators of antitumor efficacy were tested in transient transfection and RNA interference experiments. RESULTS: Cyclin E1 mRNA and protein expressions were suppressed after sorafenib treatment in sorafenib-sensitive but not in sorafenib-resistant hepatocellular carcinoma cells. Changes in cyclin E2 or D1 were not correlated with sorafenib sensitivity. The knockdown of cyclin E1 expression reversed the resistance of hepatocellular carcinoma cells to sorafenib in terms of cell growth and apoptosis induction, whereas the overexpression of cyclin E1 increased the resistance to sorafenib. The growth-inhibitory and apoptosis-inducing effects of sorafenib were enhanced by flavopiridol, and Mcl-1 suppression was determined to play a critical role in mediating this enhancing effect. CONCLUSIONS: The cyclin E1 suppression in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib efficacy. The combination of sorafenib and CDK inhibitors may improve the efficacy of sorafenib in hepatocellular carcinoma. Clin Cancer Res; 22(10); 2555-64. ©2015 AACR.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Cyclin E/antagonists & inhibitors , Drug Resistance, Neoplasm/drug effects , Liver Neoplasms/drug therapy , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Niacinamide/analogs & derivatives , Oncogene Proteins/antagonists & inhibitors , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , Animals , Apoptosis/drug effects , Carcinoma, Hepatocellular/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Hep G2 Cells , Humans , Liver Neoplasms/metabolism , Male , Mice, Inbred BALB C , Mice, Nude , Niacinamide/pharmacology , RNA, Messenger/metabolism , Signal Transduction/drug effects , Sorafenib , Xenograft Model Antitumor Assays/methodsABSTRACT
Growth arrest DNA damage-inducible gene 45 (GADD45) family proteins play a crucial role in regulating cellular stress responses and apoptosis. The present study explored the prognostic and predictive role of GADD45γ in hepatocellular carcinoma (HCC) treatment. GADD45γ expression in HCC cells was examined using quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. The control of GADD45γ transcription was examined using a luciferase reporter assay and chromatin immunoprecipitation. The in vivo induction of GADD45γ was performed using adenoviral transfer. The expression of GADD45γ in HCC tumor tissues from patients who had undergone curative resection was measured using qRT-PCR. Sorafenib induced expression of GADD45γ mRNA and protein, independent of its RAF kinase inhibitor activity. GADD45γ induction was more prominent in sorafenib-sensitive HCC cells (Huh-7 and HepG2, IC50 6-7 µM) than in sorafenib-resistant HCC cells (Hep3B, Huh-7R, and HepG2R, IC50 12-15 µM). Overexpression of GADD45γ reversed sorafenib resistance in vitro and in vivo, whereas GADD45γ expression knockdown by using siRNA partially abrogated the proapoptotic effects of sorafenib on sorafenib-sensitive cells. Overexpression of survivin in HCC cells abolished the antitumor enhancement between GADD45γ overexpression and sorafenib treatment, suggesting that survivin is a crucial mediator of antitumor effects of GADD45γ. GADD45γ expression decreased in tumors from patients with HCC who had undergone curative surgery, and low GADD45γ expression was an independent prognostic factor for poor survival, in addition to old age and vascular invasion. The preceding data indicate that GADD45γ suppression is a poor prognostic factor in patients with HCC and may help predict sorafenib efficacy in HCC.
