Proteolysis-targeting chimera against BCL-XL inhibits breast cancer metastasis

Project Summary-Abstract Metastasis is the major cause of BrCa death. Most women with metastatic BrCa (stage IV) are treated mainly with systemic therapy such as hormone therapy (for estrogen receptor-positive BrCa), chemotherapy, targeted therapy, and some combinations. Current treatments are very unlikely to cure metastatic BrCa, with more than 70% death rate within 5 years of diagnosis. Therapeutic targeting BrCa metastasis is largely lacking. Here we are aiming to develop a single agent with dual targeting capability: 1) to kill metastatic cancer cells directly; 2) to kill cancer specific regulatory T cells (Tregs) hence inducing anti-cancer immunity. With an effort to search the potential molecular target, we decided to inhibit BCL-XL using an emerging novel PROTAC technology. With two lead PROTAC compounds (BCL-XL-Ps) we have recently developed, we found that both compounds can efficiently lead to the degradation of BCL-XL in vitro and in vivo. Interestingly, it appears that the BCL-XL-Ps work in all syngeneic cancer models we have tested with the strongest suppressive efficacy in breast cancer metastasis. Using multidisciplinary techniques, we believe BCL-XL-Ps kill metastatic cancer cells and Tregs simultaneously as we initially expected. The current project will define the lineage-specific role of BCL-XL in cancer cells and in Tregs. Even though the direct cancer cell killing may not be sufficient to eradicate metastatic tumor growth as shown in the preliminary data, a portion of dead cancer cells may provide sufficient auto- or neo-antigens for T cell activation. In addition, BCL-XL depletion in cancer cells sensitizes them to CD8-T cell mediated killing. The BCL-XL-Ps-mediated Treg depletion and direct activation of T cells elicits a strong anti- cancer immunity that can be harvested for cancer therapy. Simultaneous depletion of BCL-XL by BCL-XL-Ps in cancer cells further sensitize them to CD8-T cell mediated killing. Here we will study the lineage-specific roles of BCL-XL in cancer. The translational research is also strongly supported by clinical observations that BCL-XL protein expression predicts shorter patient survival in breast cancer patients. Our long-term goal is to develop the lead compound into clinic for dual targeting of cancer cells and Tregs in treating metastatic breast cancers.