Biochemical markers of bone turnover in metastatic prostate cancer

转移性前列腺癌骨转换的生化标志物

• 批准号: 7080230
• 负责人: PRIMO N. LARA
• 金额: $ 12.89万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-21 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7080230
• 关键词: bone; clinical research; hormone related neoplasm /cancer; metastasis; prostate neoplasms; serum

DESCRIPTION (provided by applicant): Bone metastasis is common in patients with prostate cancer and is a frequent source of morbidity, including bone pain or fracture. Assessment of skeletal bone metastases in these patients has been with imaging modalities. However, bone scintigraphy is not highly specific and fails to detect areas of bone degradation, a feature common to bony metastases. In addition, many patients with a clinical response to therapy characterized by a declining PSA and improved well-being may not have an immediate corresponding improvement in the bone scintigraphy scan. Thus, biochemical markers of bone metabolism in blood have been explored as indicators of bone turnover for their potential as prognostic and/or predictive variables. As part of a randomized NCI-sponsored phase II trial of a matrix metalloproteinase inhibitor in patients with hormone refractory prostate cancer with skeletal metastases, our group prospectively evaluated serum markers of bone turnover from 69 patients and correlated the results with patient outcome. We found that several baseline markers of bone formation (osteocalcin, procollagen N-terminal propeptides: PINP & PIIINP, total alkaline phosphates) and resorption (N-telopeptide, pyridinoline, deoxypyridinoline) in serum had statistically significant prognostic value. Data from trials employing the endothelin-A antagonist Atrasentan in prostate cancer patients showed that levels of total and bone alkaline phosphates significantly predicted time to progression. We will prospectively validate these encouraging preliminary results in a similar, larger, patient cohort through the recently initiated randomized phase III Southwest Oncology Group trial (S0421) of docetaxel/prednisone with or without the endothelin-A antagonist Atrasentan (n=706) in patients with metastatic hormone refractory prostate cancer. The hypothesis is that baseline levels of bone metabolism markers in sera collected from patients with metastatic hormone refractory prostate cancer will be of prognostic value, while serial levels of these same markers will predict enhanced response and survival following therapy with a bone-targeted agent such as Atrasentan. This hypothesis will be tested through the following specific aims: 1) measure levels of selected markers of bone formation (procollagen I amino-terminal propeptides: PINP, total and bone alkaline phosphates) and resorption (N- telopeptide, deoxypyridinoline) in sera collected at baseline and serially from patients enrolled in SWOG 0421, a randomized phase III trial of docetaxel/prednisone with or without Atrasentan in patients with hormone refractory prostate cancer with skeletal metastases; 2) correlate the results of these marker studies with tumor response, progression-free survival, and overall survival to detect prognostic (baseline or pre-treatment sera) and/or predictive (serial sera) value; 3) identify prognostic groups based on baseline bone markers and other clinical and disease-related factors, and to evaluate whether change in a bone marker is a surrogate for survival in this setting.

描述（由申请人提供）：骨转移在前列腺癌患者中很常见，是发病的常见原因，包括骨痛或骨折。评估这些患者的骨转移已经与影像学方式。然而，骨肿瘤造影术的特异性不高，无法检测骨降解区域，这是骨转移瘤的共同特征。此外，许多对治疗有临床反应的患者，其特征是PSA下降和健康状况改善，但在骨密度扫描中可能没有立即相应的改善。因此，血液中骨代谢的生化标志物已被探索作为骨转换的指标，其作为预后和/或预测变量的潜力。作为一项由美国国家癌症研究所赞助的基质金属蛋白酶抑制剂治疗激素难治性前列腺癌骨转移患者的随机II期试验的一部分，我们的研究小组前瞻性地评估了69例患者的骨转换血清标志物，并将结果与患者结局相关联。我们发现，血清中骨形成（骨钙素，前胶原N-末端前肽：PINP和PIIINP，总碱性磷酸盐）和骨吸收（N-末端肽，吡啶啉，脱氧吡啶啉）的几个基线标志物具有统计学显著的预后价值。在前列腺癌患者中使用内皮素A拮抗剂阿曲生坦的试验数据显示，总碱性磷酸酶和骨碱性磷酸酶水平可显著预测疾病进展时间。我们将通过最近启动的多西他赛/泼尼松联合或不联合内皮素A拮抗剂阿曲生坦（n=706）治疗转移性激素难治性前列腺癌患者的随机III期西南肿瘤组试验（S 0421），在类似的大型患者队列中前瞻性验证这些令人鼓舞的初步结果。假设从转移性激素难治性前列腺癌患者收集的血清中骨代谢标志物的基线水平将具有预后价值，而这些相同标志物的连续水平将预测用骨靶向药物如阿曲生坦治疗后的增强的反应和存活。该假设将通过以下具体目的进行检验：1）测量骨形成的选定标志物的水平（前胶原I氨基末端前肽：PINP，总磷酸盐和骨碱性磷酸盐）和再吸收（N-端肽，脱氧吡啶啉）在基线时和从SWOG 0421中招募的患者中连续收集的血清中，一项多西他赛/泼尼松联合或不联合阿曲生坦治疗激素难治性前列腺癌伴骨转移患者的随机III期试验; 2）将这些标志物研究的结果与肿瘤反应、无进展生存期和总生存期相关联，以检测预后（基线或治疗前血清）和/或预测（系列血清）值; 3）基于基线骨标志物和其他临床和疾病相关因素鉴定预后组，并评估骨标志物的变化是否是这种情况下生存的替代物。