Grant: CIHR Fellowship

Breast cancer is the most common and the second leading cause of cancer death in women. Current treatments for breast cancer, including chemotherapy, can have dose limiting side effects. Therefore, new treatments that are safe and effective are desperately needed. Poly-ADP ribose polymerase inhibitors (PARPi) have emerged as a promising treatment for cancers with defects in the breast cancer gene (BRCA), however patients eventually stop responding to therapy. Previously, our lab has shown that PARPi increases the recruitment of a type of immune cell called macrophages which promote tumor growth and limit patient response to cancer treatment. Therefore, targeting macrophages may improve PARPi treatment. Autophagy, a process by which a cell breaks down and destroys old, damaged, or abnormal proteins and other components of the cell is essential for the tumor-promoting activity of macrophages. Furthermore, autophagy function in the cancer cell is associated with increased cancer cell growth, metastasis, and cancer treatment resistance, including PARPi treatment resistance. Therefore, here we will test how autophagy regulates the tumor-promoting activity of macrophages as well as its regulation of how cancer cells die during PARPi therapy. We will test how inhibiting autophagy may improve PARPi treatment. Our hypothesis is that inhibiting autophagy will have a two-pronged, synergistic effect in which it will 1) eliminate tumor-promoting macrophages and 2) enhance cancer cell death, and therefore will improve PARPi therapy, and patient outcomes. These findings will immediately impact patient care as PARPi and autophagy inhibitors are already approved for use in the clinical setting and thus will yield a promising novel combination therapy that may benefit a variety of cancer types.