Dual blockade of CD47 and CD24 signaling using a novel bispecific antibody fusion protein enhances macrophage immunotherapy.

CD47 and its receptor signal regulatory protein α (SIRPα) act as a dominant antiphagocytic, "don't eat me" signal. Recent studies reveal CD24 as a novel target for cancer immunotherapy by macrophages in ovarian cancer and breast cancer. However, whether simultaneous blockade of CD47 and CD24 by a bispecific antibody may result in a potential synergy is still unclear. In the present study, we for the first time designed and developed a bispecific antibody fusion protein, PPAB001 for cotargeting CD47 and CD24. Data demonstrate that simultaneous blockade of CD47/SIRPα and CD24/Siglec-10 signaling by PPAB001 potently promoted macrophage phagocytosis of tumor cells. Compared to single CD47 or CD24 targeting agents, PPAB001 was more effective in inhibiting tumor growth in both mouse 4T-1 syngeneic and human SK-OV-3 xenogeneic tumor models. Mechanistically, we found that PPAB001 therapy markedly increased the proportion of tumor-infiltrating macrophages and upregulated interleukin-6 and tumor necrosis factor-α levels that were representative macrophage inflammatory cytokines. Notably, an increased ratio of M1/M2 in tumor-infiltrating macrophages in the mice treated with PPAB001 suggested that the dual blockade may promote the transition of macrophages from M2 to M1. Taken together, our data supported the development of PPAB001 as a novel immunotherapeutic in the treatment of CD47 and CD24 double-positive cancers.

A novel synthetic chalcone derivative, 2,4,6-trimethoxy-4'-nitrochalcone (Ch-19), exerted anti-tumor effects through stimulating ROS accumulation and inducing apoptosis in esophageal cancer cells.

Esophageal cancer has always been associated with poor prognosis and a low five-year survival rate. Chalcone, a flavonoid family member, has shown anti-tumor property in several types of cancer. However, few studies reported the potency and mechanisms of action of synthetic Chalcone derivatives against esophageal squamous cell carcinoma. In this study, we designed and synthesized a series of novel chalcone analogs and Ch-19 was selected for its superior anti-tumor potency. Results indicated that Ch-19 shows a dose- and time-dependent anti-tumor activity in both KYSE-450 and Eca-109 esophageal cancer cells. Moreover, treatment of Ch-19 resulted in the regression of KYSE-450 tumor xenografts in nude mice. Furthermore, we investigated the potential mechanism involved in the effective anti-tumor effects of Ch-19. As a result, we observed that Ch-19 treatment promoted ROS accumulation and caused G2/M phase arrest in both Eca-109 and KYSE-450 cancer cell lines, thereby resulting in cell apoptosis. Taken together, our study provided a novel synthetic chalcone derivative as a potential anti-tumor therapeutic candidate for treating esophageal cancer.

The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers.

The dual tyrosine kinase (EGFR/HER2) inhibitor lapatinib is currently used to clinically treat HER2-positive breast cancer. However, a majority of patients do not respond to lapatinib therapy within 6 months. Therefore, potentiating the anti-tumor effect of lapatinib by combination treatment has a great potential to overcome the obstacle. Herein, we aim to investigate the anti-tumor activity of lapatinib in combination with brusatol and explore the potential mechanism involved in the combinatorial treatment. Our findings revealed that the Nrf2 inhibitor brusatol potently enhanced the anti-tumor effect of lapatinib against SK-BR-3, SK-OV-3 and AU565 cancer cells in a synergistic manner. Furthermore, we found that lapatinib plus brusatol more effectively decreased Nrf2 level and induced ROS generation in both SK-BR-3 and SK-OV-3 cells. Moreover, we also observed a significant reduction on the phosphorylation of HER2, EGFR, AKT and ERK1/2 in SK-BR-3 and SK-OV-3 cells when treated with lapatinib plus brusatol compared to either agent alone. More importantly, brusatol significantly augmented the anti-tumor effects of lapatinib in the SK-OV-3 xenograft model. In summary, these data provide a potential rationale for the combination of brusatol and lapatinib on the treatment of HER2-positive cancers.