We have made significant progress toward Objective 1 and 2 for this project. Over the past six months, we have continued work to examine molecular and functional changes induced by PIK3CA gene mutations in canine HSA cells. Our data reveal that PI3K inhibitors increase DNA damage greater in HSA cells with PIK3CA mutations than cells without the mutations (i.e., wild-type cells), which depends on a drug dose.
We also show that PIK3CA mutant HSA cells have strong functional activity to modulate intracellular signaling pathways in response to PI3K inhibitors. PI3K inhibitors influence not only a handful of molecules, but also many genes simultaneously: they induce changes in global gene expression. We have identified significant gene clusters that are differently regulated by PI3K inhibitors in PIK3CA mutant HSA cells by bioinformatic and computational analyses. Specifically, the PI3K inhibitors dysregulate multiple genes that are important for immune functions. The tumor niche is a pivotal tissue environment where the tumor cells maintain their cellular functions to grow and survive. Thus, therapeutic approaches by killing tumor cells and disrupting the tumor niche at the same time have potentials to inhibit tumor progression effectively.
The results of this project suggest potential approaches to develop novel chemotherapy targeting the PI3K pathway, especially in dogs with HSA where PIK3CA mutations are detected. Our work continues to define specific gene candidates that contribute to the establishment of the tumor immune niche, and it will also help develop novel combined immunotherapies for canine HSA