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

项目总结/摘要 在临床上，原发性乳腺肿瘤通常在诊断后不久就被手术切除， “无肿瘤”然而，20-40%的乳腺癌幸存者最终会转移到远处器官， 有时是手术后几年。骨转移是乳腺癌最常见的转移灶。 我们的长期目标是阐明骨转移瘤生存和进展的生物学基础， 这将通过一个富有成效的方法，为设计针对这些潜伏肿瘤细胞的治疗策略提供信息。 莱斯大学和贝勒医学院实验室之间的合作。本提案的总体目标是 是开发骨肿瘤靶向表观遗传抑制剂，并证明其对骨 微转移以及来自骨病变的进一步多器官转移。我们的初步数据 确定：（1）用双膦酸盐修饰的表观遗传抑制剂，对骨具有极好的结合亲和力， 表现出增强的体内骨转移位点靶向;和（2）用以下修饰的表观遗传抑制剂 双膦酸盐显示出抑制从骨病变转移到其他组织的活性改善， 器官;和（3）髂内动脉（IIA）注射，在我们的实验室开发，可以用来有效地模拟 骨转移灶，为评价骨转移治疗效果提供了一个强有力的平台。 转移性癌症和来自骨损伤的“转移到转移”播种。根据这些结果，第一 研究方向将集中在工程目前的表观遗传抑制剂的乳腺癌治疗与骨， 归巢部分。接下来，我们将研究它们对乳腺癌骨转移生存和进展的影响 使用同系和异种移植裸鼠模型。此外，我们将剖析分子 骨肿瘤靶向表观遗传抑制剂的益处的潜在机制。增强的治疗 这些骨特异性表观遗传抑制剂对乳腺癌的作用将为这些治疗的扩展提供信息 与其他骨癌和疾病的联系。

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.