Breast Cancer Bone Metastasis

描述（由申请人提供）：我们的题为“乳腺癌骨转移”的申请集中于我们已经在具有骨转移的乳腺癌患者的循环中鉴定的特异性生物标志物（PTHrP（12-48）和IL-8）的表征。目前，理解和治疗NIH/NCI感兴趣的疾病（如乳腺癌骨转移）的障碍是缺乏敏感和特异性的生物标志物。我们已经鉴定和验证的生物标志物谱包含PTHrP（12-48）和IL-8，并以98%和82%的灵敏度和特异性区分有和无骨转移的乳腺癌患者。这些分子有可能提高临床骨转移诊断的准确性，为肿瘤诱导的骨代谢变化提供新的机制见解，甚至可能改善乳腺癌骨转移患者结局的评估。目的1将改进我们现有的检测方法并测量患者血浆和人乳腺癌标本中的PTHrP（12-48）和IL-8。目的2探讨肿瘤源性IL-8在破骨细胞生成中的作用机制。重要的是，我们还将获得IL-8直接作用于 体内破骨细胞形成，并确定IL-8表达是否可以挽救RANKL-/-小鼠的骨硬化骨表型。目标3将其他临床相关参数（如生存率、肿瘤负荷和下一次SRE时间）与我们现有的蛋白质组数据集相关联，然后使用未经测试的存档患者血浆独立验证和鉴定相关生物标志物。提出的研究将通过提供有关乳腺癌骨转移进展的新信息来显著影响该领域。如果临床上成功，PTHrP（12-48）和IL-8有可能被用作评估乳腺癌骨转移的生化标志物，其可以预测乳腺癌负荷，甚至可能预测患者存活。

DESCRIPTION (provided by applicant): Our application entitled "Breast Cancer Bone Metastasis" is focused on the characterization of specific biomarkers (PTHrP(12-48) and IL-8) that we have identified in the circulation of breast cancer patients with bone metastasis. Currently, a barrier to understanding and treating diseases of interest to NIH/NCI, such as breast cancer bone metastasis, is the paucity of sensitive and specific biomarkers. The biomarker profile we have identified and validated contains PTHrP(12-48) and IL-8 and discriminates breast cancer patients with and without bone metastasis with a sensitivity and specificity of (98% and 82% respectively). These molecules have the potential to increase the accuracy of bone metastasis diagnosis in the clinical setting, provide new mechanistic insight into tumor-induced changes in bone metabolism and possibly even improve the assessment of breast cancer bone metastasis patient outcomes. Aim 1 will improve our existing assay and measure PTHrP(12-48) and IL-8 in patient plasma and human breast cancer specimens. Aim 2 will explore the mechanism of action of tumor-derived IL-8 in the regulation of osteoclastogenesis. Importantly, we will also obtain genetic evidence for direct effects of IL-8 on osteoclast formation in vivo and determine if IL-8 expression can rescue the osteopetrotic bone phenotype of RANKL-/- mice. Aim 3 will correlate other clinically relevant parameters such as survival, tumor burden and time-to-next SRE with our existing proteomic dataset, and then independently validate and identify the correlated biomarkers using untested archival patient plasma. The studies proposed will significantly impact the field by providing new information regarding the progression of breast cancer bone metastasis. If successful clinically, PTHrP(12-48) and IL-8 have the potential to be utilized as biochemical markers for the evaluation of breast cancer bone metastasis that may predict breast cancer burden and possibly even patient survival.