Understanding the underlying biology driving breast cancer metastasis and identifying molecular targets for the development of effective therapies to reduce breast cancer deaths.

Impact

Breast cancer metastasis, the spread of cancer from the original site to other parts of the body, is a complex and multi-step process. While metastatic breast cancer is treatable, it cannot be cured and is responsible for most deaths due to breast cancer. This makes the development of new therapeutic strategies an urgent priority for researchers such as Dr. Schneider. He was the first to recognize the importance of the protein synthesis machinery to the growth and metastasis of breast cancer cells and has been building on this finding to develop new methods to target protein production in metastatic breast cancer cells. His team has identified key pathways in this process and have developed several experimental drugs to selectively inhibit them. In addition to these studies, Dr. Schneider discovered a factor called DAP5, one part of a complex of factors involved in the synthesis of proteins necessary for tissue invasion, cell detachment, and migration—key processes required for metastasis. DAP5-mediated metastasis utilizes a mechanism of protein synthesis not previously described and the team has identified an essential protein component of the DAP5 complex, called eIF3d, which interacts with DAP5 to mediate these processes. 

Progress Thus Far

Using dynamic structural prediction models, Dr. Schneider and his team have initiated studies to determine how DAP5 and eIF3d interact and to design small molecules that can inhibit this process. In the last year, they showed that DAP5-eIF3d control the synthesis of proteins that promote cell migration, invasion, and metastasis. They also developed laboratory models to represent different stages of breast cancer from development to metastasis and used them to assess the effects of small molecule inhibitors on the metastatic process. In related work, Dr. Schneider discovered a connection between the activation of immune suppressive cells called Tregs and DAP5. Under normal conditions, Tregs help maintain immune system balance. However, Treg cells can promote cancer progression and metastasis by inhibiting the anti-tumor response initiated by immunotherapies. Triple-negative breast cancers may be less responsive to immunotherapy because of an increase in Tregs. 

What's next

Moving forward, Dr. Schneider and his team will continue to probe how the DAP5-eIF3d complex is used to promote breast cancer metastasis and to test the small molecule inhibitors they have developed. Ongoing investigations will aim to develop other agents that target this complex and test their ability to both treat and prevent metastasis in laboratory models. In addition, they will focus on the mechanism by which DAP5-eIF3d mediates Treg action and how manipulation of DAP5-eIF3d activity can be exploited to impair Treg cell immune suppression and improve the efficacy of anti-PD1 therapy.