RESUMO
BACKGROUND: Despite immunotherapy advancements for patients with advanced or metastatic non-small-cell lung cancer (NSCLC), pivotal first-line trials were limited to patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and a median age of 65 years or younger. We aimed to compare the efficacy and safety of first-line atezolizumab monotherapy with single-agent chemotherapy in patients ineligible for platinum-based chemotherapy. METHODS: This trial was a phase 3, open-label, randomised controlled study conducted at 91 sites in 23 countries across Asia, Europe, North America, and South America. Eligible patients had stage IIIB or IV NSCLC in whom platinum-doublet chemotherapy was deemed unsuitable by the investigator due to an ECOG PS 2 or 3, or alternatively, being 70 years or older with an ECOG PS 0-1 with substantial comorbidities or contraindications for platinum-doublet chemotherapy. Patients were randomised 2:1 by permuted-block randomisation (block size of six) to receive 1200 mg of atezolizumab given intravenously every 3 weeks or single-agent chemotherapy (vinorelbine [oral or intravenous] or gemcitabine [intravenous]; dosing per local label) at 3-weekly or 4-weekly cycles. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety analyses were conducted in the safety-evaluable population, which included all randomised patients who received any amount of atezolizumab or chemotherapy. This trial is registered with ClinicalTrials.gov, NCT03191786. FINDINGS: Between Sept 11, 2017, and Sept 23, 2019, 453 patients were enrolled and randomised to receive atezolizumab (n=302) or chemotherapy (n=151). Atezolizumab improved overall survival compared with chemotherapy (median overall survival 10·3 months [95% CI 9·4-11·9] vs 9·2 months [5·9-11·2]; stratified hazard ratio 0·78 [0·63-0·97], p=0·028), with a 2-year survival rate of 24% (95% CI 19·3-29·4) with atezolizumab compared with 12% (6·7-18·0) with chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilisation or improvement of patient-reported health-related quality-of-life functioning scales and symptoms and fewer grade 3-4 treatment-related adverse events (49 [16%] of 300 vs 49 [33%] of 147) and treatment-related deaths (three [1%] vs four [3%]). INTERPRETATION: First-line treatment with atezolizumab monotherapy was associated with improved overall survival, a doubling of the 2-year survival rate, maintenance of quality of life, and a favourable safety profile compared with single-agent chemotherapy. These data support atezolizumab monotherapy as a potential first-line treatment option for patients with advanced NSCLC who are ineligible for platinum-based chemotherapy. FUNDING: F Hoffmann-La Roche and Genentech Inc, a member of the Roche group.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Platina/uso terapêutico , Qualidade de Vida , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Mitochondria, which serve as the fundamental organelle for cellular energy and metabolism, are closely linked to the growth and survival of cancer cells. This study aims to identify and assess Sideroflexin1 (SFXN1), an unprecedented mitochondrial gene, as a potential prognostic biomarker for lung adenocarcinoma (LUAD). METHODS: The mRNA and protein levels of SFXN1 were investigated based on the Cancer Genome Atlas (TCGA) LUAD dataset, and then validated by real-time quantitative PCR, Western Blotting and immunohistochemistry from our clinical samples. The clinical correlation and prognostic value were evaluated by the TCGA cohort and verified via our clinical dataset (n = 90). The somatic mutation, drug sensitivity data, immune cell infiltration and single-cell RNA sequencing data of SFXN1 were analyzed through public databases. RESULTS: SFXN1 was markedly upregulated at both mRNA and protein levels in LUAD, and high expression of SFXN1 were correlated with larger tumor size, positive lymph node metastasis, and advanced clinical stage. Furthermore, SFXN1 upregulation was significantly associated with poor clinical prognosis. SFXN1 co-expressed genes were also analyzed, which were mainly involved in the cell cycle, central carbon metabolism, DNA repair, and the HIF-1α signaling pathway. Additionally, SFXN1 expression correlated with the expression of multiple immunomodulators, which act to regulate the tumor immune microenvironment. Results also demonstrated an association between SFXN1 expression and increased immune cell infiltration, such as activated CD8 + T cells, natural killer cells (NKs), activated dendritic cells (DCs), and macrophages. LUAD patients with high SFXN1 expression exhibited heightened sensitivity to multiple chemotherapies and targeted drugs and predicted a poor response to immunotherapy. SFXN1 represented an independent prognostic marker for LUAD patients with an improved prognostic value for overall survival when combined with clinical stage information. CONCLUSIONS: SFXN1 is frequently upregulated in LUAD and has a significant impact on the tumor immune environment. Our study uncovers the potential of SFXN1 as a prognostic biomarker and as a novel target for intervention in LUAD.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/genética , Biomarcadores , Genes Mitocondriais , Neoplasias Pulmonares/genética , Prognóstico , RNA Mensageiro , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) can lead to life-threatening pneumonitis, and pre-existing interstitial lung abnormalities (ILAs) are a risk factor for checkpoint inhibitor pneumonitis (CIP). However, the subjective assessment of ILA and the lack of standardized methods restrict its clinical utility as a predictive factor. This study aims to identify non-small cell lung cancer (NSCLC) patients at high risk of CIP using quantitative imaging. METHODS: This cohort study involved 206 cases in the training set and 111 cases in the validation set. It included locally advanced or metastatic NSCLC patients who underwent ICI therapy. A deep learning algorithm labeled the interstitial lesions and computed their volume. Two predictive models were developed to predict the probability of grade ≥ 2 CIP or severe CIP (grade ≥ 3). Cox proportional hazard models were employed to analyze predictors of progression-free survival (PFS). RESULTS: In a training cohort of 206 patients, 21.4% experienced CIP. Two models were developed to predict the probability of CIP based on different predictors. Model 1 utilized age, histology, and preexisting ground glass opacity (GGO) percentage of the whole lung to predict grade ≥ 2 CIP, while Model 2 used histology and GGO percentage in the right lower lung to predict grade ≥ 3 CIP. These models were validated, and their accuracy was assessed. In another exploratory analysis, the presence of GGOs involving more than one lobe on pretreatment CT scans was identified as a risk factor for progression-free survival. CONCLUSIONS: The assessment of GGO volume and distribution on pre-treatment CT scans could assist in monitoring and manage the risk of CIP in NSCLC patients receiving ICI therapy. CLINICAL RELEVANCE STATEMENT: This study's quantitative imaging and computational analysis can help identify NSCLC patients at high risk of CIP, allowing for better risk management and potentially improved outcomes in those receivingICI treatment.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Estudos de Coortes , Pulmão/patologia , Pneumonia/patologia , Tomografia Computadorizada por Raios X , Estudos RetrospectivosRESUMO
BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and concurrent mutations have a poor prognosis. This study aimed to examine anlotinib plus icotinib as a first-line treatment option for advanced NSCLC carrying EGFR mutation with or without concurrent mutations. METHODS: This phase 2, single-arm, multicenter trial (ClinicalTrials.gov NCT03736837) was performed at five hospitals in China from December 2018 to November 2020. Non-squamous NSCLC cases with EGFR-sensitizing mutations were treated with anlotinib and icotinib. The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. RESULTS: Sixty participants were enrolled, including 31 (52%) and 29 (48%) with concurrent mutations and pathogenic concurrent mutations, respectively. The median follow-up was 26.9 (range, 15.0-38.9) months. ORR and DCR were 68.5% and 98.2%, respectively. Median PFS was 15.1 (95%CI: 12.6-17.6) months which met the primary endpoint, median DoR was 13.5 (95%CI: 10.0-17.1) months, and median OS was 30.0 (95%CI: 25.5-34.5) months. Median PFS and OS in patients with pathogenic concurrent mutations were 15.6 (95%CI: 12.5-18.7) months and not reached (95%CI: 17.46 months to not reached), respectively. All patients experienced TRAEs, including 26 (43%) and 1 (1.7%) who had grade ≥ 3 and serious treatment-related adverse events (TRAEs). CONCLUSIONS: Anlotinib combined with icotinib was effective and well-tolerated as a first-line treatment option for EGFR mutation-positive advanced NSCLC with or without concurrent mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03736837.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Estudos Prospectivos , Receptores ErbB/genética , MutaçãoRESUMO
AIMS: To investigate the predictive value of baseline C-reactive protein (CRP) levels on the efficacy of chemotherapy plus immune checkpoint inhibitors (ICI) in patients with advanced lung squamous cell carcinoma (LSCC). MATERIALS AND METHODS: In this retrospective multicenter study spanning from January 2016 to December 2020, advanced LSCC patients initially treated with chemotherapy or a combination of chemotherapy and ICI were categorized into normal and elevated CRP subgroups. The relationship between CRP levels and treatment outcomes was analyzed using multivariate Cox proportional hazards models and multivariate logistic regression, focusing primarily on the progression-free survival (PFS) endpoint, and secondarily on overall survival (OS) and objective response rate (ORR) endpoints. Survival curves were generated using the Kaplan-Meier method, with the log-rank test used for comparison between groups. RESULTS: Of the 245 patients evaluated, the 105 who received a combination of chemotherapy and ICI with elevated baseline CRP levels exhibited a significant reduction in PFS (median 6.5 months vs. 11.8 months, HR, 1.78; 95% CI: 1.12-2.81; p = 0.013) compared to those with normal CRP levels. Elevated CRP was identified as an independent risk factor for poor PFS through multivariate-adjusted analysis. However, among the 140 patients receiving chemotherapy alone, baseline CRP levels did not significantly influence PFS. Furthermore, within the combination therapy group, there was a notable decrease in the ORR (51% vs. 71%, p = 0.035), coupled with a significantly shorter OS (median 20.9 months vs. 31.5 months, HR, 2.24; 95% CI: 1.13-4.44; p = 0.033). CONCLUSION: In patients with advanced LSCC, elevated baseline CRP levels were identified as an independent predictive factor for the efficacy of combination therapy with chemotherapy and ICI, but not in chemotherapy alone. This suggests that CRP may be a valuable biomarker for guiding treatment strategies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Proteína C-Reativa , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Estudos Retrospectivos , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , PulmãoRESUMO
Rearranged during transfection ( RET ) fusions and epidermal growth factor receptor ( EGFR ) mutations are potent oncogenic drivers in patients with nonsmall cell lung cancer (NSCLC), but rarely co-exist. Concurrent RET/EGFR mutations have been reported in patients with NSCLC who develop resistance to EGFR tyrosine kinase inhibitors but are even less frequent in treatment-naïve patients. Consequently, there is no standard treatment for RET/EGFR -mutated NSCLC. We report a case of RET/EGFR mutant NSCLC successfully treated with the oral, potent, highly selective RET inhibitor selpercatinib (160â mg daily for 28-day cycles) in an ongoing phase II study in Chinese patients with NSCLC (LIBRETTO-321). The patient, a female nonsmoker, was diagnosed with de-novo left lung adenocarcinoma with neuroendocrine differentiation, and a RET fusion was detected by next-generation sequencing testing. The patient had two tumors in the pleura, a third in the subcarinal lymph node, and a nontarget tumor in the pleura. Pleural biopsy analysis confirmed a RET fusion KIF5B (K15;R12) and an EGFR exon 19 deletion. The patient achieved a partial response (PR) with selpercatinib (absence of target tumors in pleura and reduction in the size of lymph node tumor). The PR persisted for 14.7â months, with disease progression in the nontarget lesion in the pleura and a new lesion in the liver (the PR had persisted), resulting in the discontinuation of selpercatinib. The only notable adverse event was grade 3 elevated transaminase, that was effectively managed by dose reduction. These data may support the use of selpercatinib in patients with RET/EGFR co-mutated NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , População do Leste Asiático , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Ensaios Clínicos Fase II como AssuntoRESUMO
BACKGROUND: Conteltinib (CT-707) is a potent second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) showing promising anti-tumor activities in preclinical studies. This study aimed to assess the safety, pharmacokinetic (PK), and efficacy of conteltinib in patients with ALK-positive non-small cell lung cancer (NSCLC). METHODS: In this multicenter, single-arm, open-label, first-in-human phase 1 study, conteltinib was taken orally at doses of 50 to 800 mg quaque die (QD) in a dose-escalation phase. If the response was observed in a dose cohort of the dose-escalation phase, dose expansion was started. The primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and adverse events assessed by investigators. RESULTS: Between April 13, 2016, and February 8, 2020, 64 ALK-positive NSCLC patients were enrolled, including 41 (64.1%) patients with ALK TKI-naïve and 23 (35.9%) patients who received crizotinib previously. In the dose-escalation phase, 26 patients were treated with conteltinib at doses of 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, 600 mg, and 800 mg QD. One DLT event was reported at the dose of 600 mg. MTD was not reached. Overall, 58 (90.6%) patients experienced treatment-related adverse events (TRAEs) and 9 (14.1%) patients had grade ≥ 3 TRAEs. The most common TRAEs were diarrhea (46 [71.9%]), serum creatinine elevated (29 [45.3%]), aspartate aminotransferase elevated (25 [39.1%]), and nausea (24 [37.5%]). Among 39 ALK TKI-naïve patients, the overall response rate (ORR) was 64.1% (25 of 39; 95% confidence interval [CI], 47.2-78.8), median progression-free survival (PFS) was 15.9 months (95% CI, 9.26-23.3), and median duration of response (DoR) was 15.0 months (95% CI, 9.06-25.8). Among 21 patients who received crizotinib previously, the ORR was 33.3% (7 of 21; 95% CI, 14.6-57.0), median PFS was 6.73 months (95% CI, 4.73-8.54), and median DoR was 6.60 months (95% CI, 3.77-13.3). CONCLUSIONS: In this study, conteltinib showed manageable safety profile, favorable PK properties, and anti-tumor activity in advanced ALK-positive NSCLC patients. The recommended phase 2 dose was determined to be 600 mg QD for ALK TKI-naïve patients and 300 mg bis in die (BID) for patients who received crizotinib previously. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02695550.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Crizotinibe/efeitos adversos , Quinase do Linfoma Anaplásico , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina QuinasesRESUMO
BACKGROUND: Small cell lung cancer is an aggressive form of lung cancer with poor prognosis. Combined serum biomarkers may give us more information and predictive value. METHODS: We retrospectively analyzed data and samples collected from 120 small cell lung cancer patients who had undergone surgery in Tianjin Medical University Cancer Institute and Hospital between June 2014 and November 2016. Correlations between serum biomarker levels and survival parameters were analyzed and prognostic factors were identified. RESULTS: By univariate analysis, limited disease (p < 0.001), more than 4 cycles of first line chemotherapy (p = 0.002), thoracic irradiation (p < 0.001), PCI (p = 0.013)), higher SCCA level (p = 0.058), and normal LDH level (p = 0.027) were significantly correlated with a good PFS. By multivariate analysis, clinical stage, number of chemotherapy cycles, thoracic irradiation, PCI, and SCCA level were independent prognostic factors for PFS. Higher ProGRP or NSE level with higher LDH, higher NSE with higher D-dimer had poor prognostic index. CONCLUSIONS: We observed that NSE, CEA, and CYFRA 21-1 were closely associated with tumor burden. The combination of NSE and ProGRP with LDH and D-dimer worked as prognostic factors for tumor progression in SCLC patients.
Assuntos
Neoplasias Pulmonares , Intervenção Coronária Percutânea , Carcinoma de Pequenas Células do Pulmão , Antígenos de Neoplasias , Biomarcadores Tumorais , Humanos , Queratina-19 , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Fosfopiruvato Hidratase , Prognóstico , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/terapiaRESUMO
Lymphatic metastasis is facilitated by lymphangiogenic growth factor vascular endothelial growth factor-C (VEGFC) that is secreted by some primary tumors. We previously identified tumor necrosis factor superfamily 15 (TNFSF15), a blood vascular endothelium-derived cytokine, in lymphatic endothelial cells, as a key molecular modulator during lymphangiogenesis. However, the effect of TNFSF15 on tumor lymphatic metastasis and the underlying molecular mechanisms remain unclear. We report here that TNFSF15, which is known to inhibit primary tumor growth by suppressing angiogenesis, can promote lymphatic metastasis through facilitating lymphangiogenesis in tumors. Mice bearing tumors induced by A549 cells stably overexpressing TNFSF15 exhibited a significant increase in densities of lymphatic vessels and a marked enhancement of A549 tumor cells in newly formed lymphatic vessels in the primary tumors as well as in lymph nodes. Treatment of A549 cells with TNFSF15 results in upregulation of VEGFC expression, which can be inhibited by siRNA gene silencing of death domain-containing receptor-3 (DR3), a cell surface receptor for TNFSF15. In addition, TNFSF15/DR3 signaling pathways in A549 cells include activation of NF-κB during tumor lymphangiogenesis. Our data indicate that TNFSF15, a cytokine mainly produced by blood endothelial cells, facilitates tumor lymphangiogenesis by upregulating VEGFC expression in A549 cells, contributing to lymphatic metastasis in tumor-bearing mice. This finding also suggests that TNFSF15 may have potential as an indicator for prognosis evaluation.
Assuntos
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metástase Linfática/patologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Regulação para Cima/fisiologia , Fator C de Crescimento do Endotélio Vascular/metabolismo , Células A549 , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Linfangiogênese/fisiologia , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologiaRESUMO
BACKGROUND/AIMS: The malignant biological behavior of gastric cancer(GC) is not only determined by cancer cells alone, but also closely regulated by the microenvironment. Fibroblasts represent a large proportion of the components in the tumor microenvironment, and they promote the development of disease. Currently, accumulating evidence suggests that exosomes can function as intercellular transport systems to relay their contents, especially microRNAs(miRNAs). METHODS: First, we detected the highly-expressed level of miR-27a in exosomes isolated from gastric cancer cells by qRT-PCR. MiR-27a -over-expressed models in vitro and in vivo were established to investigate the transformation of cancer-associated fibroblasts observed by Western blotting, and the malignant behavior of gastric cancer cells using the methods CCK8 and Transwell. Moreover, the downregulation of CSRP2 in fibroblasts was used to evaluate the promotion of malignancy of gastric cancer using the methods CCK8 and Transwell. RESULTS: In this study, we found a marked high level of miR-27a in exosomes derived from GC cells. miR-27a was found to function an oncogene that not only induced the reprogramming of fibroblasts into cancer-associated fibroblasts(CAFs), but also promoted the proliferation, motility and metastasis of cancer cells in vitro and in vivo. Conversely, CAFs with over-expression of miR-27a could pleiotropically increase the malignant behavior of the GC cells. For the first time, we revealed that CSRP2 is a downstream target of miR-27a. CSRP2 downregulation could increase the proliferation and motility of GC cells. CONCLUSION: Thus, this report indicates that miR-27a in exosomes derived from GC cells has a crucial impact on the microenvironment and may be used as a potential therapeutic target in the treatment of GC.
Assuntos
Exossomos/metabolismo , MicroRNAs/metabolismo , Animais , Fibroblastos Associados a Câncer/citologia , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica , Regulação para Baixo , Exossomos/genética , Feminino , Humanos , Proteínas com Domínio LIM/antagonistas & inibidores , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Proteínas Musculares/antagonistas & inibidores , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologiaRESUMO
Gastric cancer is a common malignancy with limited treatment options and poor prognosis. Introduction of novel pathways of gastric cancer will provide candidates for target therapy. Hepatocyte growth factor activator inhibitor type 1 is an integral-membrane proteinase inhibitor. Hepatocyte growth factor activator inhibitor type 1 abnormality is found in various cancers and correlates with tumor progression and metastasis. However, the mechanisms underlying the dysregulation of hepatocyte growth factor activator inhibitor type 1 expression in gastric cancer remain unclear. Although microRNAs have been reported to be involved in the development of cancer, the roles of miR-221 and miR-222 in gastric cancer have not been reported yet. In this study, we showed that hepatocyte growth factor activator inhibitor type 1 protein was downregulated, while miR-221 and miR-222 were significantly increased in gastric cancer tissues. Bioinformatic predictions and luciferase assay verified that the 3'-untranslated region of the HAI-1 gene is a direct target site for miR-221 and miR-222. Overexpression of miR-221 and miR-222 in MGC-803 cells leads to the inhibition of hepatocyte growth factor activator inhibitor type 1 protein expression, thus promoting cell proliferation and migration; whereas knockdown of miR-221 and miR-222 showed opposite effects. Moreover, we found that the expression level of hepatocyte growth factor activator protein was increased when hepatocyte growth factor activator inhibitor type 1 was knocked down in MGC-803 cells. Thus, gastric cancer is probably an autocrine tumor, and the antitumor mechanism of hepatocyte growth factor activator inhibitor type 1 in vitro might be mediated by regulating the expression of hepatocyte growth factor activator protein. Therefore, our data illustrated a novel pathway comprising miR-221and miR-222 and hepatocyte growth factor activator inhibitor type 1 in gastric cancer, which is a potential target for future clinical use.
Assuntos
MicroRNAs/genética , Proteínas Secretadas Inibidoras de Proteinases/biossíntese , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/biossíntese , Proteínas Secretadas Inibidoras de Proteinases/genética , Neoplasias Gástricas/patologiaRESUMO
OBJECTIVE: The aim of the study was to establish an effective prognostic nomogram for esophageal squamous cell carcinoma after radical esophagectomy followed by adjuvant chemotherapy in those previously untreated patients. METHODS: The clinicopathological data from 328 patients who underwent radical esophagectomy followed by adjuvant chemotherapy or not at the Tianjin Medical University Cancer Institute and Hospital between 2006 and 2010 were retrospectively studied. Nomograms which predicted survival of esophageal squamous cell carcinoma were established based on the Cox proportional hazards regression model. To determine its predictive accuracy and discriminatory capacity, the concordance index and calibration curve were calculated after bootstrapping in the internal validation. An external validation of 76 patients in 2011 was prospectively studied at the same institution. To verify the performance of the nomogram, the comparison between the nomogram and Tumor-Node-Metastasis staging system was conducted. RESULTS: The 5-year overall survival was 43.1% in the primary cohort. Based on multivariate analyses, five independent prognostic variables including gender, tumor length, T stage, N stage and chemotherapy cycles were selected to build the nomograms to predict disease-free survival and overall survival. The concordance index of the nomogram to predict overall survival was 0.71 (95% confidence interval, 0.63-0.79), which was superior to the predictive power of Tumor-Node-Metastasis staging system (0.64) in the primary cohort. Meanwhile, the calibration curve showed good accuracy between predictive and actual overall survival. In the validation cohort, the concordance index (0.77) and calibration plot displayed favorable performances. The other nomogram to predict disease-free survival also performed well. CONCLUSIONS: The prognostic nomogram provided individualized risk estimate of survival in patients after esophagectomy followed by adjuvant chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Esofagectomia , Nomogramas , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Quimioterapia Adjuvante , China/epidemiologia , Intervalo Livre de Doença , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
We previously identified five miRNAs (miR-1, miR-20a, miR-27a, miR-34a, and miR-423-5p) that are up-regulated in gastric cancer. The goal of this study was to investigate the value of these miRNAs as potential biomarkers for predicting chemosensitivity and prognosis in metastatic or recurrent gastric cancer patients who received first-line chemotherapy. A total of 82 patients with metastatic or recurrent GC receiving first-line chemotherapy were included in our study. The expression levels of the five miRNAs were evaluated using hydrolysis probe-based stem-loop quantitative reverse transcription polymerase chain reaction (qRT-PCR) in individual samples before first-line chemotherapy. Patients receiving first-line chemotherapy with fluoropyrimidine combined with oxaliplatin or paclitaxel were chosen for the chemosensitivity analysis. The relationships between expression of the five-miRNAs and clinicopathological parameters, response to chemotherapy and prognosis were analyzed statistically. Patients with higher miRNA1 expression levels tended to have a higher rate of liver metastasis, and higher miRNA34a expression levels occurred more frequently in males (P = 0.022). The expression of the remaining three miRNAs showed no obvious relationship to any of the clinicopathological features. The partial response rates of the patients with high miRNA1 expression and low miRNA1 expression were 11.1% and 23.1%, respectively (P = 0.048). Similar results were observed for miRNA27a (the partial response rate was 7.7% vs. 25.9%, P = 0.018). Patients with up-regulated miRNA27a expression had a significantly worse overall survival (OS) than patients with lower miRNA27a expression (P = 0.024). In patients with MRGC, miRNA27a is a potential biomarker for predicting resistance to fluoropyrimidine-based chemotherapy and a novel prognostic marker for gastric cancer.
Assuntos
Biomarcadores Tumorais/sangue , MicroRNAs/sangue , Recidiva Local de Neoplasia/sangue , Neoplasias Gástricas/sangue , Idoso , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Prognóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologiaRESUMO
Cancer patients frequently present with activated coagulation pathways and thrombocytosis, which are potentially associated with tumor progression and prognosis. However, the prognostic value of abnormal plasma fibrinogen and platelet levels for the treatment of pancreatic cancer is unclear. The purpose of our study was to evaluate the prognostic value of plasma fibrinogen and platelet levels in pancreatic cancer, and to devise a prognostic model to identify the patients with greatest risk for a poor overall survival. One hundred and twenty-five patients diagnosed with pancreatic ductal adenocarcinoma in our hospital between May 2000 and June 2005 were included in this study. The plasma fibrinogen and platelet levels were examined before treatment and analyzed along with patient clinicopathological parameters and overall survival. The foundation of prognostic model was based on the risk factors according to the Cox proportional hazard model. The incidence of hyperfibrinogenemia and thrombocytosis was 24.8% (31/125) and 15.2% (19/125), respectively. The mean fibrinogen concentration differed significantly between the early (I/II) and late (III/IV) stage patients (3.19 ± 0.70 vs. 3.65 ± 0.90 g/l, p = 0.008). Patients with a higher concentration of plasma fibrinogen and platelets had a worse prognosis (p < 0.05). There also existed a significant correlation between higher fibrinogen/platelet levels and distant organ metastasis (p < 0.05, respectively). Bivariate correlation analysis showed that plasma fibrinogen levels correlated significantly with platelet levels (p = 0.000). Multivariate analysis revealed that pretreatment plasma fibrinogen levels (p = 0.027), tumor stage (p = 0.026) and distant metastasis (p = 0.027) were independent prognostic factors. The median survival time for the low-, intermediate-, and high-risk groups was 9.6 months (95% CI 6.2-13.0), 3.8 months (95% CI 2.3-5.3), and 2.3 months (95% CI 0.9-3.7), respectively (p = 0.000). Pretreatment plasma fibrinogen and platelet levels closely correlated with tumor progression, metastasis and overall survival in pancreatic cancer. The foundation of prognostic model may help us identify the greatest risk populations with pancreatic cancer.
Assuntos
Plaquetas/metabolismo , Neoplasias Pancreáticas/sangue , Idoso , Progressão da Doença , Feminino , Fibrinogênio/metabolismo , Humanos , Masculino , Metástase Neoplásica , Neoplasias Pancreáticas/mortalidade , Prognóstico , Fatores de Risco , Análise de SobrevidaRESUMO
OBJECTIVE: Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor characterized by initial sensitivity to chemotherapy, followed by the development of drug resistance. The underlying mechanisms of resistance in SCLC have not been fully elucidated. Aldo-keto reductase family 1 member C3 (AKR1C3), is known to be associated with chemoradiotherapy resistance in diverse tumors. We aim to evaluate the prognostic significance and immune characteristics of AKR1C3 and investigate its potential role in promoting drug resistance in SCLC. METHODS: 81 postoperative SCLC tissues were used to analyze AKR1C3 prognostic value and immune features. The tissue microarrays were employed to validate the clinical significance of AKR1C3 in SCLC. The effects of AKR1C3 on SCLC cell proliferation, migration, apoptosis and tumor angiogenesis were detected by CCK-8, wound healing assay, transwell assay, flow cytometry and tube formation assay. RESULTS: AKR1C3 demonstrated the highest expression level compared to other AKR1C family genes, and multivariate cox regression analysis identified it as an independent prognostic factor for SCLC. High AKR1C3 expression patients who underwent chemoradiotherapy experienced significantly shorter overall survival (OS). Furthermore, AKR1C3 was involved in the regulation of the tumor immune microenvironment in SCLC. Silencing of AKR1C3 led to the inhibition of cell proliferation and migration, while simultaneously promoting apoptosis and reducing epithelial-mesenchymal transition (EMT) in SCLC. CONCLUSION: AKR1C3 promotes cell growth and metastasis, leading to drug resistance through inducing EMT and angiogenesis in SCLC.
RESUMO
Elevated infiltration of tumor-associated macrophages (TAMs) drives tumor progression and correlates with poor prognosis for various tumor types. Our research identifies that the ablation of the Pim-1 proto-oncogene (PIM1) in non-small cell lung cancer (NSCLC) suppresses TAM infiltration and prevents them from polarizing toward the M2 phenotype, thereby reshaping the tumor immune microenvironment (TME). The predominant mechanism through which PIM1 exerts its impact on macrophage chemotaxis and polarization involves CC motif chemokine ligand 2 (CCL2). The expression level of PIM1 is positively correlated with high CCL2 expression in NSCLC, conferring a worse overall patient survival. Mechanistically, PIM1 deficiency facilitates the reprogramming of TAMs by targeting nuclear factor kappa beta (NF-κB) signaling and inhibits CCL2 transactivation by NSCLC cells. The decreased secretion of CCL2 impedes TAM accumulation and their polarization toward a pro-tumoral phenotype. Furthermore, Dual blockade of Pim1 and PD-1 collaboratively suppressed tumor growth, repolarized macrophages, and boosted the efficacy of anti-PD-1 antibody. Collectively, our findings elucidate the pivotal role of PIM1 in orchestrating TAMs within the TME of NSCLC and highlight the potential of PIM1 inhibition as a strategy for enhancing the efficacy of cancer immunotherapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Quimiocina CCL2 , Neoplasias Pulmonares , NF-kappa B , Proteínas Proto-Oncogênicas c-pim-1 , Microambiente Tumoral , Macrófagos Associados a Tumor , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Microambiente Tumoral/imunologia , Humanos , Quimiocina CCL2/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Camundongos , NF-kappa B/metabolismo , Animais , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Proto-Oncogene Mas , Macrófagos/imunologia , Macrófagos/metabolismo , Linhagem Celular Tumoral , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Transdução de Sinais , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismoRESUMO
Acquired resistance is inevitable in the treatment of non-small cell lung cancer (NSCLC) with osimertinib, and one of the primary mechanisms responsible for this resistance is the epithelial-mesenchymal transition (EMT). We identify upregulation of the proviral integration site for Moloney murine leukemia virus 1 (PIM1) and functional inactivation of glycogen synthase kinase 3ß (GSK3ß) as drivers of EMT-associated osimertinib resistance. Upregulation of PIM1 promotes the growth, invasion, and resistance of osimertinib-resistant cells and is significantly correlated with EMT molecules expression. Functionally, PIM1 suppresses the ubiquitin-proteasome degradation of snail family transcriptional repressor 1 (SNAIL) and snail family transcriptional repressor 2 (SLUG) by deactivating GSK3ß through phosphorylation. The stability and accumulation of SNAIL and SLUG facilitate EMT and encourage osimertinib resistance. Furthermore, treatment with PIM1 inhibitors prevents EMT progression and re-sensitizes osimertinib-resistant NSCLC cells to osimertinib. PIM1/GSK3ß signaling is activated in clinical samples of osimertinib-resistant NSCLC, and dual epidermal growth factor receptor (EGFR)/PIM1 blockade synergistically reverse osimertinib-resistant NSCLC in vivo. These data identify PIM1 as a driver of EMT-associated osimertinib-resistant NSCLC cells and predict that PIM1 inhibitors and osimertinib combination therapy will provide clinical benefit in patients with EGFR-mutant NSCLC.
Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Receptores ErbB , Glicogênio Sintase Quinase 3 beta , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-pim-1 , Transdução de Sinais , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Camundongos , Linhagem Celular Tumoral , Mutação/genética , Camundongos Nus , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Transcrição da Família Snail/genética , Indóis , PirimidinasRESUMO
BACKGROUND: Tunlametinib (HL-085) is a novel, highly selective MEK inhibitor with substantial clinical activities in patients with NRAS-mutant melanoma. This phase I study evaluated the safety and preliminary efficacy of tunlametinib plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors. METHODS: Patients with confirmed advanced BRAF V600-mutant solid tumors who had progressed on or shown intolerance or no available standard therapies were enrolled and received tunlametinib plus vemurafenib. This study consisted of a dose-escalation phase and a dose-expansion phase. Primary end points of this study were safety, the recommended phase II dose (RP2D), and preliminary efficacy. RESULTS: From August 17, 2018 to April 19, 2022, 72 patients were enrolled. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. The RP2D for BRAF V600-mutant non-small cell lung cancer (NSCLC) patients was tunlametinib 9 mg plus vemurafenib 720 mg, twice daily (BID, bis in die). Until the data cut-off date of December 15, 2023, of 33 NSCLC patients with evaluable disease, the objective response rate (ORR) was 60.6% (20/33; 95% confidence interval [CI], 42.1-77.1), the median progression free survival (PFS) was 10.5 months (95%CI, 5.6-14.5) and median duration of response (DoR) was 11.3 months (95%CI, 6.8-NE). At the RP2D, ORR was 60.0% (9/15; 95% CI, 32.3-83.7), the median PFS was 10.5 months (95%CI, 5.6 -NE) and median DoR was 11.3 months (95%CI, 3.9-NE). Of 24 colorectal cancer patients with evaluable disease, the ORR was 25.0% (6/24; 95% CI, 5.6-NE). All 72 patients had treatment-related adverse events (TRAEs), and the most common grade 3-4 TRAEs were anemia (n = 13, 18.1%) and blood creatine phosphokinase increased (n = 10, 13.9%). Tunlametinib was absorbed rapidly with Tmax of 0.5-1 h. Vemurafeinib did not influence the system exposure of tunlametinib and vice versa, indicating no drug-drug interaction for this combination. CONCLUSIONS: Tunlametinib (HL-085) plus vemurafenib had a favorable safety profile and showed promising antitumor activity in patients with BRAF V600-mutant solid tumors. The RP2D for NSCLC was tunlametinib 9 mg BID plus vemurafeinib 720 mg BID. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03781219.
RESUMO
INTRODUCTION: Extensive-stage SCLC (ES-SCLC) prognosis remains poor. The phase 3 RATIONALE-312 study aimed to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment for ES-SCLC. METHODS: RATIONALE-312 is a randomized, double-blind, placebo-controlled trial, conducted in the People's Republic of China. Eligible patients with previously untreated ES-SCLC were randomized 1:1 to receive four cycles of tislelizumab 200 mg or placebo, with etoposide plus carboplatin or cisplatin intravenously every 3 weeks, followed by tislelizumab 200 mg or placebo as maintenance. The primary end point was overall survival (OS). Secondary end points included progression-free survival and safety. RESULTS: Between July 22, 2019 and April 21, 2021, 457 patients were randomized to tislelizumab (n = 227) or placebo (n = 230), plus chemotherapy. Baseline demographics were generally balanced between arms. At the data cutoff (April 19, 2023), the median study follow-up was 14.2 months (interquartile range: 8.6-25.3). Tislelizumab plus chemotherapy exhibited a statistically significant OS benefit versus placebo plus chemotherapy (stratified hazard ratio = 0.75 [95% confidence interval (CI): 0.61-0.93]; one-sided p = 0.0040; median: 15.5 [95% CI: 13.5-17.1] versus 13.5 mo [95% CI: 12.1-14.9], respectively). Progression-free survival was significantly improved in the tislelizumab versus placebo arm (stratified hazard ratio = 0.64 [95% CI: 0.52-0.78]; p < 0.0001; median: 4.7 [95% CI: 4.3-5.5] versus 4.3 mo [95% CI: 4.2-4.4], respectively). Grade greater than or equal to 3 treatment-related adverse events were reported in 86% of patients in each treatment arm and were mostly hematologic. CONCLUSIONS: Tislelizumab plus chemotherapy exhibited statistically significant clinical benefit and manageable safety compared with placebo plus chemotherapy as first-line treatment in patients with advanced ES-SCLC.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Etoposídeo , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Masculino , Método Duplo-Cego , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Etoposídeo/administração & dosagem , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Idoso , Adulto , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Garsorasib (D-1553; InventisBio, Shangai, China), a potent KRASG12C inhibitor, has shown promising antitumour activity in patients with KRASG12C-mutated (ie, Gly12Cys) non-small-cell lung cancer (NSCLC) in a phase 1 study. We report results from a phase 2 study conducted to evaluate the efficacy and safety of garsorasib in patients with locally advanced or metastatic KRASG12C-mutated NSCLC. METHODS: This open-label, multicentre, single-arm, phase 2 trial enrolled adult patients with KRASG12C-mutated NSCLC who had previously been treated with platinum-based chemotherapy and immune checkpoint inhibitors from 43 hospitals in China. Participants received 600 mg garsorasib orally twice per day. Tumour assessments were performed at baseline, at the end of every two cycles (of 21 days) for the first eight cycles, and at the end of every three cycles thereafter. The primary endpoint was objective response rate (ORR) as assessed by an independent review committee (IRC) following the guidelines in Response Evaluation Criteria in Solid Tumours, version 1.1. Efficacy and safety were assessed in all patients who received at least one dose of garsorasib. This trial is registered at ClinicalTrials.gov, NCT05383898, and is active but no longer recruiting. FINDINGS: From June 17, 2022, to May 17, 2023, of 225 patients screened for eligibility, 123 patients were enrolled and treated with garsorasib. Of these 123 participants, the median age was 64 years (IQR 59-68), 108 (88%) were male and 15 (12%) were female. At data cutoff (Nov 17, 2023), the median follow-up duration was 7·9 months (IQR 6·3-10·4), and 82 (67%) of 123 patients had discontinued treatment. The IRC-confirmed ORR was 50% (61 of 123 patients; 95% CI 41-59). 117 (95%) of 123 patients reported treatment-related adverse events, with 61 (50%) experiencing grade 3 or higher events. The most common types of adverse events of grade 3 or higher associated with garsorasib were hepatic and gastrointestinal events, including increased liver enzymes, such as aspartate aminotransferase (21 [17%] of 123 participants), alanine aminotransferase (19 [15%] of 123 participants), and gamma-glutamyltransferase (28 [23%] of 123 participants); nausea (2 [2%] of 123 participants); and vomiting (2 [2%] of 123 participants). No new safety signals were identified, and most of the adverse events were well managed. INTERPRETATION: The results show that garsorasib has a high response rate, long duration of response, and an acceptable and manageable safety profile in patients with previously treated KRASG12C-mutated NSCLC. Garsorasib potentially provides a promising treatment option for this patient population. FUNDING: InventisBio.