Grant: Project Grant

Because cancer cells have lost checkpoints that healthy cells have, they have increased levels of DNA damage. This DNA damage causes particular problems during replication, when cells make a copy of their DNA. (When a cell divides, both cells should have a complete set of the DNA.) Cancer cells therefore have higher stress levels than healthy cells and they rely on certain remaining pathways to survive this stress. An important signaling pathway after replication stress is initiated by a protein called ATR. Another important signaling protein is Wee1. Our unpublished studies indicate that cancer cells strongly rely on these two proteins to survive, and inhibiting the function of Wee1 or ATR by selective drugs is harmful to the cancer cells. But if both, ATR and Wee1, are inhibited, the cancer cell killing is stronger than one would expect from just an additive effect of each drug alone. We call this "Synergy". This promises to get a much better therapy response with a novel treatment combining the two drugs. Furthermore we see the synergistic killing in cancer cells at doses well tolerated by healthy cells. This is important to avoid side effects which are due to killing of healthy cells. In our preclinical studies, using human cancers grown in mice, we will test the combination treatment targeting ATR and Wee1 for the ability to inhibit tumour growth and prevent metastasis. In addition we hope to understand which tumours are most likely to respond to the combined inhibition of Wee1 and ATR inhibition. Because the Wee1 and ATR inhibitors we are using for our studies are drugs already being tested in the clinic (on their own, not in combination), our knowledge could soon find application in actual patient treatment. Because our lab focuses on breast cancer, we first will study that type of cancer. Breast cancer is the most common cancer in women in Canada and worldwide.