Role of PI3K-gamma in Cancer Growth and Survival

Research has demonstrated that PI3K-gamma plays an important role in maintaining the immunosuppressive nature of tumor-associated macrophages within the tumor microenvironment (TME) and myeloid-derived suppressor cells (MDSCs). Targeting these pro-tumor, immunosuppressive cells represents an emerging approach within the field of cancer immunotherapy, and inhibition of PI3K-gamma by eganelisib represents a novel approach to targeting this immunosuppressive microenvironment.

Our preclinical research has demonstrated that blockade of PI3K-gamma by treatment with eganelisib leads to a shift in the type of macrophages present in the TME from macrophages associated with suppression of the body’s pro-tumor immune response, known as the M2 phenotype, to macrophages that are supportive of a pro-inflammatory, anti-tumor immune response, known as the M1 phenotype1. In preclinical studies, treatment with eganelisib in tumor models was shown to increase the M1 to M2 macrophage ratio, the number of T cells that attack the tumor, and the production of pro-inflammatory, anti-tumor cytokines. 

Overcoming Resistance to Checkpoint Inhibition

In recent years, checkpoint inhibitors have shown promising results as a treatment for multiple types of cancer, but most patients do not respond, and most who do respond eventually become resistant to and require treatment with an additional therapy. Our preclinical studies in a number of tumor models demonstrated that resistance to checkpoint inhibition is associated with increased numbers of tumor-associated macrophages and is directly mediated by the immunosuppressive activity of these macrophages on T cells. Furthermore, the data demonstrated that inhibition of PI3K-gamma by eganelisib led to enhanced anti-tumor cytotoxic T cell activity, particularly when combined with checkpoint inhibitors. These data demonstrated that eganelisib treatment was able to reverse the lack of response to checkpoint inhibitors in models that were initially resistant to checkpoint inhibition as a single therapy2.

 

[1] Kaneda, M., Messer, K., Ralainirina, N., Li, H., et al. PI3Kγ is a molecular switch that controls immune suppression. Nature, 2016 Nov;539:437–442.

[2] De Henau, O., Rausch, M., Winkler, D., Campesato, L., et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature, 2016 Nov;539:443-447.