Abstract B054: The synergistic effect of PLAG on the antitumor efficacy of AC-regimen via alleviating neutrophil tumor infiltration on breast tumor xenograft model

Abstract

Abstract Background: Tumor microenvironments (TME) promote tumor growth and induction of metastasis along with the strong presence of tumor-infiltrating neutrophil (TIN), which further contributes to abnormal tumor growth and metastasis. From this tumor-prone environment, we hypothesize that the effective destruction of TIN may enhance the therapeutic efficacy of chemotherapy for reducing the tumor. In this study, we investigated the synergistic effect of PLAG in the MDA-MB-231 breast cancer xenograft model concomitantly treated with the AC-regimen in modulating the effect of TIN. Methods: MDA-MB-231 breast cancer xenograft model was used for evaluation of the tumor growth in the AC-regimen alone and PLAG co-treated animals. AC-regimen was delivered via intraperitoneal injection twice a week with a dose of 2/20 and 5/50 mpk (Doxorubicin/Cyclophosphamide) and PLAG was daily administered with 100 and 250 mpk. Tumor growth was measured in 3-day intervals. Neutrophil chemotaxis-related chemokines, CXCL1/2/8 and circulating neutrophils were also evaluated in a 2-week interval. Expression of apoptosis-related molecular markers (Bax/Bak) and TIN in the tumor lesion was analyzed by immunohistochemistry (IHC) staining. Results: PLAG has synergistic effects on decreasing the tumor burden in the PLAG and AC-treated xenograft model. In AC-treated groups with 2/20 or 5/50 mpk, retardation of tumor growth was observed from the calculated tumor size and regulation of apoptosis-associated markers was proved by TUNEL assay and IHC. Modulated chemokine expression from tumor burden and subsequent neutrophil recruitment were also detected in proportion to the tumor mass. The measured tumor sizes in the PLAG co-treated group were consistently smaller than those from the AC-regimen alone group till the mice were sacrificed. It was confirmed that the tumor burden of the PLAG co-treated group with 5/50 AC-regimen was significantly decreased in a concentration-dependent manner compared to the AC-regimen alone group (p<0.05). Surprisingly, in 250 mpk PLAG co-treated group, tumor seemed completely regressed in 2 test mice on the sacrifice day. In accordance with the tumor size regression, significantly reduced chemokine expression and TIN in the PLAG co-treated group was demonstrated from the IHC and chemokine analysis. The tumor growth inhibition and reduced chemokine expression and TIN were also observed from the PLAG alone treated groups. Conclusion: Taken together, PLAG has synergistic effects on relieving tumor burden concomitantly treated with AC-regimen. Combining the AC-regimen for the the apoptotic effect of tumors and the PLAG treatment to regulate the number of TIN will be a promising treatment modality for eliminating malignant tumors. Citation Format: GUEN TAE KIM, SUN YOUNG YOON, KI-YOUNG SOHN, MYUNG-HWAN KIM, JAE WHA KIM. The synergistic effect of PLAG on the antitumor efficacy of AC-regimen via alleviating neutrophil tumor infiltration on breast tumor xenograft model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B054. doi:10.1158/1535-7163.TARG-19-B054