Effects Of Bet Inhibitors On The Proliferation Of Small Cell Lung Cancerdomains

Study objective: This study was designed to detect the expression of BRD4 and c-Myc in patients with SCLCand follow-up their survival data to evaluate the relationship between BRD4 and c-Myc expression and survival outcome of SCLC patients.Finally,we want to confirm the anti-cancer efficacy and safety of new compounds targeting double functional domains of BRD4 through xenograft and patients derived xenograft of squamous cell carcinoma.The results will provide theoretical basis and experimental basis for the development of new anti-tumor drugs for SCLC.Methods: We detected the expression of BRD4 and c-Myc in 137 SCLC patients from April 2012 to December 2017 by immunohistochemistry and evaluated the relationship between the expression level and clinical features and survival prognosis.Finally,we confirmed the anti-cancer efficacy and safety of new compounds targeting double functional domains of BRD4 through xenograft and patients derived xenograft of SCLC.Result:(1)In 137 SCLC patients,the positive rate of BRD4 and c-Mycwere 25.5% and 21.8% respectively by immunohistochemistry.The co-expression of c-Myc and BRD4 was 54.3%.(2)For limited-stage SCLC,the expression level of BRD4 and c-Myc were negatively correlated with OS,(p=0.02 and p=0.03).The median OS of high and low BRD4 groups were 27.3months and 33.9 months respectively.The median OS of high and low c-Myc groups were 28.8 months and 33.9 months respectively.There were no statistically significance between the expression levels of BRD4 andc-Mycand OS with advanced SCLC(p=0.42 and p=0.39).(3)We observed NHWD-870 and NHWD-870 HCL significantly inhibited tumor growth of SCLC in nude mice(p=0.000 and p =0.019).(4)NHWD-870 HCL combined with EP resulted synergistic effects against SCLC tumors(p=0.001).(5)NHWD-870 HCL can significantly suppressed the growth of human SCLC(p=0.013)without obvious adverse reactions.Conclusion:The high expression of BRD4 and c-Myc in patients with limited SCLC was associated with poor prognosis,and they were highly consistent.NHWD-870 and NHWD-870 HCL can significantly inhibited the proliferation of SCLC tumor in vivo(CDX or PDX).NHWD-870 HCL combined with EP had the synergistic effect against SCLC tumors.