Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a nasty disease with extremely high malignancy and poor prognosis. Annexin A3 (ANXA3) is a potential prognosis biomarker, displaying an excellent correlation of ANXA3 overexpression with patients' poor prognosis. Silencing the expression of ANXA3 effectively inhibits the proliferation and metastasis of TNBC, suggesting that ANXA3 can be a promising therapeutic target to treat TNBC. Herein, we report a first-in-class ANXA3-targeted small molecule (R)-SL18, which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells. (R)-SL18 directly bound to ANXA3 and increased its ubiquitination, thereby inducing ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model. Furthermore, (R)-SL18 could reduce the β-catenin level, and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells. Collectively, our data suggested that targeting degradation of ANXA3 by (R)-SL18 possesses the potential to treat TNBC.

Research progresses of Annexin A3 in malignant tumors / 医学研究生学报

Annexin A3(ANXA3), is a crucial member of the membrane associated protein superfamily, whose function research is still insufficient. Previous researches have confirmed that Annexin A3 is involved in a variety of cellular processes, but its function is still unclear. Accumulating evidences suggested that Annexin A3 is closely related to various malignant tumors, and plays an important role in tumor development, metastasis, invasion and drug resistance. Therefore, Annexin A3 is expected to be a new therapeutic target for malignant tumors. This article provided an overview about the role of Annexin A3 in malignant tumors.

Predictive value of Annexin A3 protein expression in peripheral blood and tumor tissue for platinum resistance in ovarian epithelial cancer / 重庆医学

Objective To compare the values of peripheral blood and tumor tissue Annexin A3 protein expressions for predictinge platinum resistance in ovarian epithelial cancer. Methods A total of 72 cases of newly treated ovarian epithelial cancer and undergoing platinum based chemotherapy after surgery,and completely followed up in this hospital from February 2010 to February 2012 were selected and divided into the platinum-sensitive group(54 cases) and platinum-resistant group(18 cases) according to the platinum resistance evaluation criteria. Peripheral blood Annexin A3 level was detected by chemiluminescence immunoassay. Tumor tissue Annexin A3 level was detected by adopting the immunohistochemical staining. The predictive value of peripheral blood and tumor tissue Annexin A3 for predicting platinum resistance was analyzed by drawing the ROC curve. Results The peripheral blood Annexin A3 level in the platinum-sensitive group was significantly lower than that in the platinum-resistant group,the difference was statistically significant(P<0.05), the positive rate of tumor tissue Annexin A3 expression in the platinum sensitivity group was significantly lower than that of platinum-resistant group(P<0.05). The median survival time in peripheral blood Annexin A3 low concentration group was significantly higher than that of high concentration group(31.2 months vs. 20.4 months, P<0.05). The median survival time in tissue Annexin A3 low expression group was significantly higher than that in the high expression group (35.2 months vs. 23.1 months P<0.05). The multivariate analysis showed that the level of Annexin A3 expression in serum and tumor tissue were the independent risk factor for affecting platinum resistance (all P<0.05). The area of curve (AUC) of peripheral blood Annexin A3 in predicting platinum resistance was 0. 821, which of tissue Annexin A3 in predicting platinum was 0. 763, peripheral blood Annexin A3 for predicting platinum resistance was significantly higher than tissue Annexin A3 (P< 0.05). Conclusion The expression levels of Annexin A3 protein in peripheral blood and tumor tissue are significantly increased in the patients with platinum resistant ovarian cancer,the predictive value of Annexin A3 protein in peripheral blood for platinum resistance is better than that of tissue Annexin A3 protein.

Effects of high Annexin A3 expression on apoptosis and proliferation of gastric cancer MGC-803 cells / 临床与实验病理学杂志

Purpose To eva1uate the effects of Annexin A3 on pro1iferation and apoptosis of gastric cancer ce11s. Methods The re-combinant p1asmid pYr-ads-4-Annexin A3 was constructed and ana1yzed by restriction ana1ysis and sequencing and was transfected into MGC803 ce11s. The stab1e transfectants were obtained after screening with G418. Western b1ot ana1ysis was used to examine the expres-sion of Annexin A3 before and after transfection. CCK8 assay,c1one assay and f1ow cytometry were used to study the effects of Annexin A3 on pro1iferation and apoptosis of MGC803 ce11s. Results The recombinant p1asmid pYr-ads-4-Annexin A3 was successfu11y con-structed. Western b1otting resu1ts indicated that the Annexin A3 expression was significant1y higher in ce11s transfected with pYr-ads-4-Annexin A3 compared with ce11s transfected with empty vectors and un-transfected ce11s( P<0. 05 ). CCK8 assay resu1ts showed the number of ce11s transfected with pYr-ads-4-Annexin A3 was significant1y higher than those transfected with empty vectors and un-trans-fected ce11s(P<0. 05). Moreover,the number of c1one in ce11s transfected with pYr-ads-4-Annexin A3 was significant1y higher than the other two groups(P<0. 05). Important1y,high Annexin A3 expression inhibited to apoptosis of MGC803 ce11s(P<0. 05). Con-clusion Annexin A3 expression p1ay important ro1es in tumorigenesis of gastric cancer. Annexin A3 cou1d promote the pro1iferation and inhibited apoptosis of gastric cancer ce11s and it might be a potentia1 target for gastric cancer treatment.