Effect of Aerobic Exercise on Genomic Signatures of Prostate Cancer Prognosis

描述(申请人提供)：前列腺癌是美国男性中最常见的癌症，2012年有超过241,000例新诊断。近一半确诊的男性患有早期、低级别疾病，可能是积极监测(AS)的良好对象。AS是一种重要的管理选择，因为它减少了过度治疗，包括标准前列腺癌治疗方法的严重副作用(例如，大小便失禁、勃起功能障碍)。然而，AS没有得到充分利用，因为目前的临床测试在区分惰性前列腺癌和侵袭性前列腺癌方面并不完美。此外，最初选择AS的男性中，约有15%最终在没有生物进展的情况下寻求根治治疗，这是由于知道自己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缓解AS特异性焦虑的策略可以极大地减少低风险前列腺癌的过度治疗，并有利于公众健康。我们报道，在前列腺癌确诊后，剧烈的体力活动和快步行走与前列腺癌进展或死亡减少约60%相关，在两个不同的前列腺癌队列中。虽然令人信服，但这些研究并没有讨论确诊后增加有氧运动是否有利于改变前列腺癌的生物学。我们的团队和其他人已经识别和验证了新的前列腺癌基因组特征，这些特征可以预测低风险前列腺癌患者的不良临床结果，并证明了短期生活方式干预可以改变前列腺中的基因表达。因此，我们建议进行一项随机对照试验，以评估在加州大学旧金山分校和杜克大学的120名前列腺癌患者中，24周有监督有氧运动和日常护理是否影响三个有效的前列腺癌基因组信号的表达。被分配到锻炼臂的男性将参加一个单独定制的跑步机步行计划，其中包括每周五次30-45分钟的锻炼，心肺健康水平的50%-80%(三人在监督下，两人在家里)。我们还将研究有氧运动对肿瘤和正常组织中与癌症相关的通路(例如生长因子信号、血管生成、DNA修复)的mRNA表达的整体影响；以及有氧运动是否与常规护理相比减少了与AS相关的焦虑和总体压力。常规前列腺活检的AS方案为研究有氧运动对前列腺癌生物学的纵向影响提供了一个独特的机会。这项随机对照试验的结果将提供必要的基本证据，以支持关于运动和前列腺癌进展的决定性的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.