Songzhi Wei

Aim: Pilocytic astrocytomas (PAs) are a common adolescent malignancy. We evaluated the effects of the betaine stachydrine on human PA cells as well as its associated molecular mechanism(s). Materials & methods: Various experiments assessing stachydrine's effects on the human PA cell line Res186 were performed. Results & conclusion: Stachydrine dose-dependently suppressed proliferation and colony formation in Res186 cells with no such effect on normal astrocytes. Stachydrine downregulated CXCR4 transcription through enhancing IκBα-based NF-κB inhibition. Stachydrine promoted apoptosis and cyclin D1/p27Kip1-associated G0/G1 phase arrest in a CXCR4/ERK- and CXCR4/Akt-dependent manner. Stachydrine suppressed MMP-associated migration and invasiveness via inhibiting CXCR4/Akt/MMP-9/2 and CXCR4/ERK/MMP-9/2 pathway activity. Stachydrine inhibits the viability, migration and invasiveness of human PA cells via inhibiting CXCR4/ERK and CXCR4/Akt signaling.

Purpose: Breast cancer is the most common type of cancer and the leading cause of cancer-related death in women worldwide. In this study, we aimed to construct an inflammatory response-related gene model for predicting the immune status and prognosis of breast cancer patients. Methods: We obtained the inflammatory response-related genes from the Molecular Signatures Database. Furthermore, we used univariate Cox regression analysis, the least absolute shrinkage and selection operator (LASSO) regression analysis, and multivariate Cox regression to construct an inflammatory response-related gene signature (IRGS) model based on dataset obtained from The Cancer Genome Atlas (TCGA). Patients were consequently categorized into high-risk and low-risk groups. Kaplan-Meier analysis was used to compare the overall survival (OS) of high-risk and low-risk groups. Following that, we validated the model using a dataset (GSE96058) acquired from Gene Expression Omnibus (GEO) database. Univariate and multivariate Cox analyses were used to determine the independent prognostic value of the IRGS in the TCGA and GSE96058 cohorts. A nomogram was constructed to predict the OS in the TCGA cohort. Further, we used Gene Set Enrichment Analysis (GSEA), CIBERSORT, and single-sample Gene Set Enrichment Analysis (ssGSEA) to evaluate the associations of IRGS with immune-associated pathways and immune infiltration. Finally, the relationship between the expression of the signature genes and drug sensitivity was conducted using Pearson correlation analysis. Results: We established an IRGS to stratify breast cancer patients into the low-risk and high-risk groups. In both the training and validation sets, patients in the high-risk group had significantly shorter OS than those in the low-risk group. The risk score was significantly correlated with the clinical characteristics and could be used as a tool to predict the prognosis of breast cancer. Moreover, we found that the IRGS risk score was an independent predictor of OS in breast cancer patients, and a nomogram model based on IRGS risk score and other clinical factors could effectively predict the prognosis of breast cancer patients. Furthermore, the IRGS risk score was correlated with immune characteristics and was inversely associated with the abundance of immune cell infiltration. Patients with a low IRGS risk score had higher expression levels of immune checkpoint genes, suggesting that IRGS can be used as a potential indicator for immunotherapy. Finally, we found that the expression levels of prognostic genes were significantly correlated with tumor cell sensitivity to chemotherapeutic drugs. Conclusion: Overall, these findings suggest that the IRGS can be used to predict the prognosis and immune status of breast cancer patients and provide new therapeutic targets for the treatment of these patients.

e13065 Background: Fulvestrant is used after aromatase inhibitor (AI) failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using anlotinib, a novel multi-target tyrosine kinase inhibitor, may delay fulvestrant resistance in patients (pts) and thus improve its efficacy. This single-arm, phase II trial aims to evaluate the efficacy and safety of the combined regimen in pts with HR-positive and HER2-negative, previously AI treated, locally advanced or metastatic breast cancer. Methods: The key enrolled criteria were women aged 18 years or older of any menopausal status (premenopausal or perimenopausal women received ovarian function suppression), ECOG PS 0-1, histologically confirmed HR-positive and HER2-negative breast cancer, and disease relapse within 12 months after a more than 24 months AI adjuvant setting or disease progress after a more than 6 months AI metastatic setting. Eligible pts received 500 mg fulvestrant by intramuscular injection on days 1 and 15 of cycle one and then on day one of each subsequent cycle (28 days). Pts were also given 12 mg oral anlotinib once daily for 2 weeks, followed by a week off in a 21-day cycle. The primary endpoints is progression-free survival (PFS) and the secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Results: 30 pts have been enrolled from Aug 2021 to Dec 2023. After a median follow-up time of 12.9 months (95% CI, 9.0-16.8), the overall median PFS was 6.4 months (95% CI 3.4-9.5) and the mOS has not reached. In the 29 pts whose efficacy could be evaluated, the ORR was 20.7% (95% CI, 8.0-39.7) and the DCR was 79.3% (95% CI, 60.3-92.0), with partial response and stable disease recorded in 6 and 17 pts. The CBR was 41.4% (95% CI, 23.5-61.1), with 6 pts reach SD for more than 6 months. Pts who have not received CDK 4/6 inhibitors previously had longer PFS (14.8 months, 95% CI 3.7-25.9) than those who have received CDK 4/6 inhibitors (4.6 months, 95% CI 3.0-6.3) in the subgroup analysis (HR=0.33, P=0.038). At the same time, we find pts who have not received systemic chemotherapy previously also had longer PFS (9.7 months, 95% CI 6.0-13.2) than those who have received systemic chemotherapy (5.5 months, 95% CI 3.6-7.4) (HR=0.47, P=0.12). TEAEs of any grade were observed in 90.0% of pts, and the frequent AEs included hypertension (43.3%), wight loss (20.0%), proteinuria (20.0%), increased TSH (20.0%), and hand-foot syndrome (20.0%). Grade 3 TEAEs occurred in 11 (36.7%) pts, the most common of which was hypertension (26.7%). Dose reductions or discontinuation of anlotinib occurred in 12 (40.0%) pts. Conclusions: Anlotinib combined with fulvestrant showed a promising efficacy with an acceptable safety profile for patients with metastatic breast cancer previously treated with AI. Further results are expected. Clinical trial information: NCT05075512 .