Amongst women in the United States, breast cancer is the most common cancer and the second leading cause of cancer-related deaths. Worldwide, it is the leading cause of cancer-related deaths among women. Triple-negative breast cancers (TNBCs), a well-defined subtype of breast cancer that lacks specific hormonal and membrane receptors, represent a particularly aggressive form of breast cancer. TNBCs, accounting for 10-24% of all breast cancers, grow rapidly and develop metastases affecting vital organs, resulting in poor overall survival. More effective therapeutic agents for TNBCs are critically needed. Recently, we and others identified that a pro-survival protein, XBP1, promotes the growth...

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Amongst women in the United States, breast cancer is the most common cancer and the second leading cause of cancer-related deaths. Worldwide, it is the leading cause of cancer-related deaths among women. Triple-negative breast cancers (TNBCs), a well-defined subtype of breast cancer that lacks specific hormonal and membrane receptors, represent a particularly aggressive form of breast cancer. TNBCs, accounting for 10-24% of all breast cancers, grow rapidly and develop metastases affecting vital organs, resulting in poor overall survival. More effective therapeutic agents for TNBCs are critically needed. Recently, we and others identified that a pro-survival protein, XBP1, promotes the growth and spread of TNBCs. Therefore, inhibiting the activation of this protein is a promising therapeutic strategy for treating TNBCs. Through screening a library of more than 100,000 drug-like chemicals, we discovered a class of compounds that effectively block XBP1 activation in tumor cells. One compound called 3,6-DMAD is especially potent and is a good candidate for further development. In the proposed project, we will synthesize additional chemically similar compounds to identify those with even greater potency. We will also characterize the molecular mechanism through which these compounds prevent XBP1 activation. Finally, we will test our most promising compounds in TNBC functional studies in cell culture and in clinically relevant breast cancer animal models. We will compare the efficacy of these new drugs with ones that are currently in clinical use for TNBCs. We expect to achieve the proposed goals within the 3-year project time and have developed a multidisciplinary team to work towards this goal. Our results will facilitate the translation of the most promising XBP1 inhibitors into potentially curative treatment strategies for TNBCs.

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