Breast Cancer Bone Metastasis

描述(由申请人提供)：我们的名为“乳腺癌骨转移”的申请集中于我们在乳腺癌骨转移患者循环中确定的特定生物标记物(PTHrP(12-48)和IL-8)的特征。目前，理解和治疗NIH/NCI感兴趣的疾病，如乳腺癌骨转移，的一个障碍是缺乏敏感和特异的生物标记物。我们已经确定和验证的生物标志物包括PTHrP(12-48)和IL-8，用于区分乳腺癌患者是否有骨转移，其敏感性和特异性分别为98%和82%。这些分子有可能在临床环境中提高骨转移诊断的准确性，为肿瘤引起的骨代谢变化提供新的机制见解，甚至可能改善对乳腺癌骨转移患者预后的评估。目的1改进现有的检测方法，检测患者血浆和人乳腺癌标本中甲状旁腺素相关蛋白(12-48)和IL-8的含量。目的2探讨肿瘤来源的IL-8在破骨细胞生成调控中的作用机制。重要的是，我们还将获得IL-8直接影响人类健康的遗传证据。 体内破骨细胞的形成，并确定IL-8的表达是否能挽救RANKL-/-小鼠的骨化表型。AIM 3将与我们现有的蛋白质组数据集关联其他临床相关参数，如生存率、肿瘤负担和下一次SRE时间，然后使用未经测试的档案患者血浆独立验证和识别相关的生物标记物。拟议的研究将通过提供有关乳腺癌骨转移进展的新信息，对该领域产生重大影响。如果临床成功，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，可能预测乳腺癌的负担，甚至可能预测患者的生存。

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.