| BackgroundApatinib is a novel oral small molecule anti-angiogenesis inhibitor developed in China,which inhibits tumor angiogenesis and exerts anti-tumor effects mainly by highly selective inhibition of VEGFR-2 tyrosine kinase activity and blocking the signal transduction pathway after VEGF binding to its receptor.Phase II and III clinical studies have demonstrated its effectiveness and acceptable safety profile in locally advanced/advanced gastric cancer or gastroesophageal junction cancer that has progressed after 2nd-line chemotherapy.However,the efficacy and safety of apatinib in elderly patients with gastric cancer is controversial due to the small number of elderly patients enrolled in these two pivotal studies.Elderly patients have special physiological characteristics and may combine more complications,especially hypertension and hyperalgesia(one study reported that the proportion of hypertension among elderly patients with gastric cancer can reach to65.7%),and the bone marrow reserve function of elderly patients is poor.Among them,hypertension was the most common adverse events(AEs),with an incidence of 69.5%,followed by hand-foot syndrome(45.6%)and bone marrow suppression(33.3%).Whether the treatment of apatinib in elderly patients with gastric cancer affects patients’ comorbidities and whether patients’ comorbidities affect the safety and efficacy of apatinib is still unclear and needs to be further explored and studied.In addition,the lack of appropriate markers for early diagnosis of gastric cancer is one of the major reasons for the poor overall survival.On the other hand,the lack of molecular markers that can accurately guide molecular typing and individualized diagnosis and treatment for patients in progressive and advanced stages also leads to unsatisfactory outcomes for these patients.In recent years,long non-coding RNAs(lncRNAs)have gained attention as a potential new tumor markers.There is increasing evidence that some lncRNAs are dysregulated in many tumors,and their abnormal expression is closely related to tumorigenesis,development,invasion and metastasis.Further studies of lncRNAs are of great significance to find molecular markers,prognostic indicators and targeted therapeutic drugs for gastric cancer.Our research team has performed high-throughput sequencing of gastric cancer tissue and paired para-cancer tissue,and found 69 new lncRNAs which have significantly different expression level for gastric cancer tissue and paired para-cancer tissue.Part 1 Efficacy and safety of apatinib in the treatment of elderly locally advanced/advanced gastric cancer Objective: To explore the efficacy and safety of apatinib in the treatment of elderly people with locally advanced/advanced gastric cancer Methods:(1)A single-arm,multicenter,phase II clinical study was initiated at the Affiliated Hospital of Qinghai University,Qinghai Provincial People’s Hospital,Qinghai Provincial Red Cross Hospital,Qinghai Provincial Fifth People’s Hospital and the First People’s Hospital of Yangquan City,Shanxi Province.The study was registered on Clinical Trials.gov,an authoritative international clinical trial registration platform,prior to implementation.The enrolled population was all elderly patients aged60 years and older with locally advanced or advanced gastric cancer who had progressed or were intolerant to chemotherapy after first-line or multiline chemotherapy.(2)All enrolled patients received apatinib mesylate tablets(Jiangsu Hengrui Pharmaceutical Co.,Ltd.,Lianyungang,China)at an initial dose of 500mg/day or 250 mg/day,as determined by the clinician,until the patient progressed or developed intolerable toxic reactions.(3)Patients underwent physical examination,urine routine,blood routine,fecal occult blood and biochemical tests,as well as enhanced computed tomography(CT)scans of the chest,abdomen and pelvis before enrollment.Physical examination and complete blood count were performed every 2weeks after enrollment.Urine routines,fecal occult blood and biochemical tests were performed every 4 weeks.The treatment effect was assessed by enhanced CT or enhanced magnetic resonance imaging(MRI)every two treatment cycles(8 weeks)and the results were recorded.(4)The investigators of each center regularly followed up the enrolled patients and recorded the adverse reactions of patients during the treatment process.(5)The median progression-free survival time(m PFS),overall response rate(ORR),disease control rate(DCR),median overall survival time(m OS)and incidence of adverse reactions were calculated.Results:(1)A total of 48 elderly patients with locally advanced/advanced gastric cancer were enrolled from June 2017 to September 2019.The median age of the included patients was 65.5 years(range 60-80 years),most of them were male(83.3%),89.6% had distant metastases,and 52.1% had liver metastases.(2)All enrolled patients received at least one cycle of apatinib treatment,with 27 patients(56.3%)treated with an initial dose of 500 mg and 21 patients(43.7%)with an initial dose of 250 mg;13patients(27.1%)received local therapy or chemotherapy after progression of apatinib treatment.(3)With a median follow-up of 7.62 months,the median PFS of enrolled patients was 3.00 months(95% CI,2.17-3.84),median OS was 8.10 months(95% CI,4.35-11.85),and 1-year OS rate was 22.9%.The investigator-assessed ORR was 16.7%and DCR was 72.9%.Exploratory subgroup analysis showed that patients with an ECOG PS score of 0-1 survived significantly longer than those with an ECOG PS score of 2.The m OS of these two groups of patients were 9.60 months and 3.83 months,respectively(P = 0.007).(4)The most common grade 3/4 AE in the enrolled patients was hypertension(22.9%),followed by neutropenia(4.2%)and mucosal inflammation(4.2%).The most common AEs of any grade was fatigue(58.3%).Other common AEs included abdominal pain(33.3%),proteinuria(29.2%),leukopenia(22.9%),and neutropenia(20.8%).There were no drug-related deaths among the enrolled patients.Conclusions: Apatinib is effective in the treatment of elderly patients with locally advanced or advanced gastric cancer who have undergone at least first-line chemotherapy,and has acceptable adverse effects.The most frequently occurring adverse reactions were fatigue and hypertension.Due to the small sample size of this study,the conclusions of this study need to be further validated by randomized controlled studies with more patients.Part 2 The expression and role of lncRNA TCONS＿00251376 in gastric cancerObjective: To explore the expression and function of lncRNA TCONS＿00251376 in gastric cancer.Methods:(1)Screen new differentially expressed lncRNAs by RNA sequencing and verify their differential expression by Quantitative Real-time PCR(q RT-PCR)in gastric cancer and paraneoplastic tissues,normal gastric mucosal cells and gastric cancer cell lines;(2)Detect the expression level of lncRNA TCONS＿00251376 in the nucleus and cytoplasm of cells using q RT-PCR.(3)After knock-down the expression of lncRNA TCONS＿00251376 in AGS cell,the cell proliferation ability,migration invasion ability and cell cycle changes were detected by CCK8 assay,flow cytometry,wound healing test and cell migration invasion assay.(4)Screen for genes that may interact with lncRNA TCONS＿00251376 and explore their relationship.Results:(1)Among five new differentially expressed lncRNAs,lncRNA TCONS＿00251376 was expressed at significantly higher levels in cancer tissues than in paracancerous tissues(P = 0.004)and in four gastric cancer cells(AGS,MKN45,BGC-823 and MGC-803)than in normal gastric mucosal cells(GES-1).Among them,MKN45 cell expressed the highest level,followed by AGS cell.(3)lncRNA TCONS＿00251376 mainly expressed in the nucleus of AGS cell and there was almost no expression in the cytoplasm(P < 0.001).(4)Silencing of lncRNA TCONS＿00251376 significantly reduced the proliferation rate of AGS cell(P < 0.05).(5)The apoptosis rate of AGS cell was significantly increased after silencing lncRNA TCONS＿00251376(P < 0.05).(6)After silencing lncRNA TCONS＿00251376,the percentage of AGS cell in G0/G1 phase was significantly increased(P < 0.05),and the percentage in S phase was significantly decreased(P < 0.05).(7)After silencing lncRNA TCONS＿00251376,the wound healing rate of AGS gastric cancer cell was significantly lower than that of the control group(P < 0.05).(8)The number of AGS cells crossing the chambers after silencing lncRNA TCONS＿00251376 was significantly less than that of the control group in both Transwell migration assay and invasion assay(P < 0.05).(9)Silencing of lncRNA TCONS＿00251376 significantly reduced ETV1 gene m RNA and protein expression(P < 0.05).Conclusions:(1)lncRNA TCONS＿00251376 was significantly expressed in gastric cancer tissues in para-cancerous tissues.(2)The expression of lncRNA TCONS＿00251376 was significantly higher in gastric cancer cells than in normal gastric mucosal cells.(3)lncRNA TCONS＿00251376 promotes the growth of AGS cell and enhances its migration and invasion ability.(4)lncRNA TCONS＿00251376 worked by upregulating the expression of ETV1 protein. |
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