Modulation of Epigenetic Target in the Bone to Treat Breast Cancer Metastasis

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PROJECT SUMMARY/ABSTRACT In the clinic, primary breast tumors are usually surgically removed soon after diagnosis, often leaving patients “tumor-free”. However, 20-40% of breast cancer survivors will eventually suffer metastasis to distant organs, sometimes years after surgeries. Bone metastasis is the most frequently occurring metastasis of breast cancer. Our long-term goals are to elucidate the biology underlying the survival and progression of bone metastases, which will inform the design of therapeutic strategies against these latent tumor cells, through a fruitful collaboration between labs at Rice University and Baylor College of Medicine. The overall goal of this proposal is to develop bone tumor-targeting epigenetic inhibitors and demonstrate their efficacy against bone micrometastases as well as further multi-organ metastases seeding from bone lesions. Our preliminary data establish that: (1) epigenetic inhibitors modified with bisphosphonates, have superb binding affinity for bone, and exhibit enhanced bone metastasis sites targeting in vivo; and (2) epigenetic inhibitors modified with bisphosphonates exhibited improved activities for inhibiting metastatic seeding from bone lesions to other organs; and (3) an intra-iliac artery (IIA) injection, developed in our lab, can be used to effectively model the bone metastatic niche, providing a powerful platform for evaluating the therapeutic efficacy against bone metastatic cancers and “metastasis-to-metastasis” seeding from bone lesions. Based on these results, the first research direction will focus on engineering current epigenetic inhibitors for breast cancer therapy with bone- homing moiety. Next, we will study their effects on the survival and progression of breast cancer bone metastases using both syngeneic and xenograft nude mouse models. Furthermore, we will dissect the molecular mechanisms underlying the benefits of bone tumor-targeting epigenetic inhibitors. An enhanced therapeutic profile for these bone-specific epigenetic inhibitors on breast cancer will inform the extension of these treatments to other bone cancers and diseases.