Joshua Saldivar, PhD

Developing a new therapeutic strategy for aggressive breast cancers.

Impact

One of the most important and universal hallmarks of aggressive breast cancer is the continuous proliferation of cancer cells, allowing uncontrolled tumor growth. Faster proliferating cancers are more aggressive, harder to treat, and lead to poorer patient outcomes. Cells proliferate by following a precisely ordered series of phases, collectively referred to as the cell cycle, and the precise order of these phases is needed for cells to maintain rapid proliferation. A promising, though still experimental, approach to treating highly proliferative breast cancers utilizes pharmacological drugs that inhibit a protein that performs essential functions in a phase of the cell cycle called ATR (ataxia-telangiectasia and Rad3-related).. Clinical studies of ATR inhibitors are ongoing, though early results suggest new therapeutic drug combinations with ATR inhibitors will be needed to increase their efficacy to treat aggressive breast cancers.

What’s next

Dr. Saldivar’s earlier research has revealed that ATR inhibition causes widespread DNA breaks during the “S phase” of the cell cycle and causes cells to stop proliferating. This abnormal progression of the cell cycle is referred to as cell cycle plasticity, where cells no longer follow the rigid series of steps during proliferation. He and his team also uncovered a pathway specific to MDM2, a protein that promotes tumor growth. This pathway is highly activated in the cells with cell cycle plasticity and point to a new therapeutic strategy to selectively kill aggressive cancer cells. Now, Dr. Saldivar and his team will test this new therapeutic strategy combining ATR inhibitors with MDM2 inhibitors, a unique drug combination could enhance the efficacy of ATR inhibitors to treat aggressive breast cancers. The team will test if the combination of ATR and MDM2 inhibitors are effective broadly across breast cancers, or if they are more effective in certain subtypes or in cancers with specific genetic drivers.