Targeting Bcl-2 and Bcl-xL: The Anti-Tumor Efficacy of AZD0466 Nanomedicine in Cancer Models

The study explores a new method to combat cancer by triggering cell death in tumor cells. The Bcl-2 protein family, which includes Bcl-2, Bcl-xL, Mcl-1, and Bcl-w, is known to enhance cell survival in cancer cells. The effectiveness of the Bcl-2 inhibitor venetoclax has been established, but a more comprehensive approach could involve targeting Bcl-2 alongside other related proteins.

AZD0466 is a novel drug that combines an active ingredient, AZD4320, with Starpharma's DEP dendrimer platform through a hydrolyzable linker. AZD4320 is a strong inhibitor of both Bcl-2 and Bcl-xL, showing a high degree of binding affinity. The new drug has been designed to be effective while reducing potential side effects of AZD4320.

In a comprehensive cell proliferation test involving 764 cancer cell lines, AZD4320 showed significant sensitivity, particularly in blood-related and small cell lung cancer (SCLC) cell lines. AZD0466 outperformed standard chemotherapy and venetoclax in several SCLC patient-derived xenograft models. In a B-ALL xenograft model, weekly doses of AZD0466 led to complete tumor disappearance at certain dosages. The drug's administration also induced the production of a specific enzyme, cleaved caspase 3, in tumors, which aligns with the measured levels of released AZD4320.

Furthermore, AZD0466 demonstrated significant anti-tumor effects in a Ri-1-DLBCL tumor model, with high doses leading to complete inhibition of tumor growth. When combined with Rituximab in the SUDHL-4 GCB DLBCL model, AZD0466 resulted in complete and lasting tumor regressions. The combination of AZD0466 with Acalabrutinib, a Bruton's Tyrosine kinase inhibitor, also resulted in complete tumor regressions in a DLBCL model.

The findings suggest that AZD0466 has potential as a standalone treatment and in combination with other drugs to enhance the effectiveness of standard therapies and BTK inhibitors in treating blood cancers. The study was presented at the 2020 Annual Meeting of the American Association for Cancer Research.