Grant: Operating Grant

Despite remarkable advances in the treatment of breast cancer one of the greatest challenges remains that of secondary tumors following seemingly successful therapy. The reasons for cancer recurrence are not fully understood however it has been thought for quite some time that it occurs because there are tumor cells that are able to escape chemotherapy and radiation to remain dormant until an opportune time to regrow. Some attribute this to the idea that within every tumor lies a small group of tumor initiating cells (TIC) that have not only the ability to escape the challenges of therapy but also to establish new tumor growth. These so called TIC only constitute about 2-10% of the total tumor and have successfully been isolated from patients because they have a unique signature of cell surface proteins called CD44 and CD49f. We recently made key observation that the Y-box binding protein-1 (YB-1) increases the abundance of CD44 and CD49f. Importantly, YB-1 also confers multi-drug resistance and we find it is highly associated with breast cancer recurrence in an analysis of over 4000 cases. Using a newly developed small molecule against YB-1, we intend to inhibit the expression of the CD44 and CD49f with the idea that this will suppress the growth of TIC and thus the re-establishment of tumors in mice. In the second part of this project, we will take advantage of a high content screening instrument that will allow us to evaluate the potential for off patent drugs to be used to inhibit the growth of TIC. In a preliminary screen, we have identified 27 drugs that could potentially block the growth of TIC however more work is needed to validate these findings. What we hope to accomplish is a better understanding of what causes TIC to grow and moreover new ways of inhibiting them such that patients at high-risk recurrence will have a better chance of living cancer free in the future.