Effect of Aerobic Exercise on Genomic Signatures of Prostate Cancer Prognosis

描述（由申请人提供）：前列腺癌是美国男性中最常诊断的癌症，2012年有超过241，000例新诊断。近一半的男性诊断为早期，低度疾病，可能是积极监测（AS）的良好候选人。AS是一种重要的管理选择，因为它减少了过度治疗，包括严重的副作用（例如，尿失禁、勃起功能障碍）的标准前列腺癌治疗。然而，AS是利用不足，因为目前的临床试验是不完善的区分惰性从侵略性前列腺癌。此外，大约15%最初选择AS的男性最终在没有生物学进展的情况下寻求治愈性治疗，这是由于知道他们患有癌症的焦虑和压力。因此，确定降低前列腺癌进展风险和减轻AS特异性焦虑的策略可以大大减少对低风险前列腺癌的过度治疗，并有益于公共卫生。我们报告了在两个不同的前列腺癌男性队列中，前列腺癌诊断后进行剧烈的体力活动和快走与前列腺癌进展或死亡减少约60%相关。虽然令人信服，但这些研究并没有解决诊断后增加有氧运动是否会有利地改变前列腺癌生物学。我们的研究小组和其他人已经确定并验证了新的前列腺基因组特征，这些特征预测了低风险前列腺癌男性的不良临床结局，并证明了前列腺中的基因表达通过短期生活方式干预而改变。因此，我们建议进行一项随机对照试验，以评估24周的监督有氧运动与常规护理是否会影响加州大学弗朗西斯科分校和杜克大学的120名患有前列腺癌的AS男性中三个经验证的前列腺基因组签名的表达。分配到运动臂的男性将参加一个单独定制的跑步机步行计划，包括每周五次30- 45分钟的训练，心肺功能为基线的50-80%（三次监督，两次在家）。我们还将研究有氧运动对肿瘤和正常组织中癌症相关途径mRNA表达的整体影响（例如生长因子信号传导、血管生成、DNA修复）;以及与常规护理相比，有氧运动是否可以减少AS相关的焦虑和整体压力。定期前列腺活检的AS协议提供了一个独特的机会来研究有氧运动对前列腺癌生物学的纵向影响。这项随机对照试验的结果将提供必要的证据，以支持一项关于运动和前列腺癌进展的确定性III期临床试验。

DESCRIPTION (provided by applicant): Prostate cancer is the most commonly diagnosed cancer among men in the United States with more than 241,000 new diagnoses in 2012. Nearly half of the men diagnosed have early stage, low-grade disease, and may be good candidates for active surveillance (AS). AS is an important management option because it reduces overtreatment, including the serious side effects (e.g., incontinence, erectile dysfunction) of standard prostate cancer therapies. However, AS is under-utilized because current clinical tests are imperfect at discerning indolent from aggressive prostate cancer. Furthermore, approximately 15% of men who initially opt for AS ultimately seek curative treatment in the absence of biological progression, due to the anxiety and stress of knowing they have cancer. Hence, identifying strategies that reduce risk of prostate cancer progression and allay AS-specific anxiety could greatly reduce the overtreatment of low risk prostate cancer and benefit public health. We reported that vigorous physical activity and brisk walking after prostate cancer diagnosis were associated with ~60% reductions in prostate cancer progression or death in two distinct cohorts of men with prostate cancer. While compelling, these studies do not address if increasing aerobic exercise after diagnosis favorably alters prostate cancer biology. Our group and others have identified and validated novel prostate genomic signatures that predict poor clinical outcomes among men with low risk prostate cancer, and demonstrated that gene expression in the prostate is modified by short-term lifestyle interventions. Thus, we propose to conduct a randomized controlled trial to evaluate whether 24 weeks of supervised aerobic exercise vs. usual care affects the expression of three validated prostate genomic signatures among 120 men with prostate cancer on AS at the University of California, San Francisco and Duke University. Men assigned to the exercise arm will participate in an individually tailored treadmill-walking program that includes five 30- 45 minute sessions per week at 50-80% of baseline cardiorespiratory fitness (three supervised, two at home). We will also examine the global effects of aerobic exercise on mRNA expression of cancer-related pathways in tumor and normal tissue (e.g. growth factor signaling, angiogenesis, DNA repair); and whether aerobic exercise reduces AS-related anxiety and overall stress compared to usual care. The AS protocol of regular prostate biopsies provides a unique opportunity to study the longitudinal effects of aerobic exercise on prostate cancer biology. The results of this randomized controlled trial will provide the essential evidence needed to support a definitive phase III clinical trial o exercise and prostate cancer progression.