Patients with advanced gastric cancer typically face a grim prognosis.This phase 1a(dose escalation)and phase 1b(dose expansion)study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemo...Patients with advanced gastric cancer typically face a grim prognosis.This phase 1a(dose escalation)and phase 1b(dose expansion)study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapyfor advanced gastric or gastroesophageal junction adenocarcinoma.The primary endpoints included maximum tolerated dose(MTD)in phase 1a and objective response rate(ORR)across phase 1a and 1b.Phase 1a tested three dose regimens of camrelizumab,apatinib,oxaliplatin,and S-1.Dose regimen 1:camrelizumab 200 mg on day 1,apatinib 250 mg every other day,oxaliplatin 100 mg/m^(2) on day 1,and S-140 mg twice a day on days 1-14.Dose regimen 2:same as dose regimen 1,but oxaliplatin 130mg/m.Dose regimen3:same as dose regimen 2,but apatinib 250 mg daily.Thirty-four patients were included(9 in phase 1a,25 in phase 1b).No dose-limiting toxicities occurred so no MTD was identified.Dose 3 was set for the recommended phase 2 doses and administered in phase 1b.The confrmed ORR was 76.5%(95%CI 58.8-89.3).The median progression-free survival was 8.4 months(95%CI 5.9-not evaluable[NE]),and the median overall survival(OS)was not mature(11.6-NE).Ten patients underwent surgery after treatment and the multidisciplinary team evaluation.Among 24 patients without surgery,the median OS was 19.6 months(7.8-NE).Eighteen patients(52.9%)developed grade≥3 treatment-emergent adverse events.Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer(ChiCTR2000034109).展开更多
Background:Considering the increase in the proportion of lung adenocarcinoma(LUAD)cases among all lung cancers and its considerable contribution to cancer-related deaths worldwide,we sought to identify novel oncogenes...Background:Considering the increase in the proportion of lung adenocarcinoma(LUAD)cases among all lung cancers and its considerable contribution to cancer-related deaths worldwide,we sought to identify novel oncogenes to provide potential targets and facilitate a better understanding of the malignant progression of LUAD.Methods:The results from the screening of transcriptome and survival analyses according to the integrated Gene Expression Omnibus(GEO)datasets and The Cancer Genome Atlas(TCGA)data were combined,and a promising risk biomarker called meiotic nuclear divisions 1(MND1)was selectively acquired.Cell viability assays and subcutaneous xenograftmodelswere used to validate the oncogenic role ofMND1 in LUADcell proliferation and tumor growth.Aseries of assays,including mass spectrometry,co-immunoprecipitation(Co-IP),and chromatin immunoprecipitation(ChIP),were performed to explore the underlying mechanism.Results:MND1 up-regulation was identified to be an independent risk factor for overall survival in LUAD patients evaluated by both tissue microarray staining and third party data analysis.In vivo and in vitro assays showed that MND1 promoted LUAD cell proliferation by regulating cell cycle.The results of the Co-IP,ChIP and dual-luciferase reporter assays validated that MND1 competitively bound to tumor suppressor Kruppel-like factor 6(KLF6),and thereby protecting E2F transcription factor 1(E2F1)from KLF6-induced transcriptional repression.Luciferase reporter and ChIP assays found that E2F1 activated MND1 transcription by binding to its promoter in a feedback manner.Conclusions:MND1,KLF6,and E2F1 form a positive feedback loop to regulate cell cycle and confer DDP resistance in LUAD.MND1 is crucial for malignant progression and may be a potential therapeutic target in LUAD patients.展开更多
基金funded by the Jiangsu Province 333 High Level Talents Project,the Beijing Xisike Clinical Oncology Research Foundation (Y-HR2019-0367)the National Natural Science Foundation of China (82102981)+3 种基金the Pukou District Social Cause Science and Technology Development Project in 2020 (S2020-21)the Pukou Branch Hospital of Jiangsu Province Hospital (Nanjing Pukou Central Hospital)General Project of Science and Technology Development Fund in 2021 (KJ2021-22)the Pukou Branch Hospital of Jiangsu Province Hospital (Nanjing Pukou Central Hospital)Major Project of Science and Technology Development Fund in 2021 (KJ2021-1)Jiangsu Hengrui Pharmaceuticals.
文摘Patients with advanced gastric cancer typically face a grim prognosis.This phase 1a(dose escalation)and phase 1b(dose expansion)study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapyfor advanced gastric or gastroesophageal junction adenocarcinoma.The primary endpoints included maximum tolerated dose(MTD)in phase 1a and objective response rate(ORR)across phase 1a and 1b.Phase 1a tested three dose regimens of camrelizumab,apatinib,oxaliplatin,and S-1.Dose regimen 1:camrelizumab 200 mg on day 1,apatinib 250 mg every other day,oxaliplatin 100 mg/m^(2) on day 1,and S-140 mg twice a day on days 1-14.Dose regimen 2:same as dose regimen 1,but oxaliplatin 130mg/m.Dose regimen3:same as dose regimen 2,but apatinib 250 mg daily.Thirty-four patients were included(9 in phase 1a,25 in phase 1b).No dose-limiting toxicities occurred so no MTD was identified.Dose 3 was set for the recommended phase 2 doses and administered in phase 1b.The confrmed ORR was 76.5%(95%CI 58.8-89.3).The median progression-free survival was 8.4 months(95%CI 5.9-not evaluable[NE]),and the median overall survival(OS)was not mature(11.6-NE).Ten patients underwent surgery after treatment and the multidisciplinary team evaluation.Among 24 patients without surgery,the median OS was 19.6 months(7.8-NE).Eighteen patients(52.9%)developed grade≥3 treatment-emergent adverse events.Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer(ChiCTR2000034109).
基金Project of Jiangsu Provincial Medical Talent,Grant/Award Number:ZDRCA2016033China Postdoctoral Science Foundation,Grant/Award Number:2018M640465+2 种基金National Natural Science Foundation of China,Grant/Award Numbers:81672295,81702265,81802277,81872378Research Program of Jiangsu Health Department,Grant/Award Number:LGY2016025Social Development Project of Jiangsu Province,Grant/Award Number:BE2019758。
文摘Background:Considering the increase in the proportion of lung adenocarcinoma(LUAD)cases among all lung cancers and its considerable contribution to cancer-related deaths worldwide,we sought to identify novel oncogenes to provide potential targets and facilitate a better understanding of the malignant progression of LUAD.Methods:The results from the screening of transcriptome and survival analyses according to the integrated Gene Expression Omnibus(GEO)datasets and The Cancer Genome Atlas(TCGA)data were combined,and a promising risk biomarker called meiotic nuclear divisions 1(MND1)was selectively acquired.Cell viability assays and subcutaneous xenograftmodelswere used to validate the oncogenic role ofMND1 in LUADcell proliferation and tumor growth.Aseries of assays,including mass spectrometry,co-immunoprecipitation(Co-IP),and chromatin immunoprecipitation(ChIP),were performed to explore the underlying mechanism.Results:MND1 up-regulation was identified to be an independent risk factor for overall survival in LUAD patients evaluated by both tissue microarray staining and third party data analysis.In vivo and in vitro assays showed that MND1 promoted LUAD cell proliferation by regulating cell cycle.The results of the Co-IP,ChIP and dual-luciferase reporter assays validated that MND1 competitively bound to tumor suppressor Kruppel-like factor 6(KLF6),and thereby protecting E2F transcription factor 1(E2F1)from KLF6-induced transcriptional repression.Luciferase reporter and ChIP assays found that E2F1 activated MND1 transcription by binding to its promoter in a feedback manner.Conclusions:MND1,KLF6,and E2F1 form a positive feedback loop to regulate cell cycle and confer DDP resistance in LUAD.MND1 is crucial for malignant progression and may be a potential therapeutic target in LUAD patients.
