Project Summary/Abstract Breast cancer is diagnosed in 1-of-8 women and is the most common type of cancer diagnosed at VCU. There are several genetically distinct subtypes of human breast cancers defined largely based on proliferative status and expression of targetable receptors such as estrogen receptors and the HER2 oncogene. The majority of the cell lines and PDX models used for breast cancer research arise from White patients of European Ancestry, however, all ancestral groups are affected by breast cancers. Over the past twenty years, there has been a clear disparity identified in the subtype of breast tumors found based on genetic ancestry, with Black patients being diagnosed more frequently with Basal-like Triple-Negative Breast Cancers, which are highly metastatic. Therefore, in these studies, we are (1) focused on developing PDX models from breast cancer patients. With these models we will (2) quantitatively determine their genetic ancestry and then (3) select models that are genetically Basal-like and obtained from Black patients so that we can (4) use these models to determine the organs that the colonize, (5) determine the genomic and proteomic profile of the tumors and metastases, (6) define efficacy of NCI-INDs of interest, with a focus on selinexor based drug combinations on cells obtained from the PDXs, and (7) identifying new therapeutic drug combinations that are effective in the metastatic setting. At the conclusion of these studies, we may have identified a new effective two-drug approach that could be useful for Basal-like patients that have exhausted the current standard-of-care approaches for treatment of metastatic breast cancer.