Energetic Factors, Lethal Prostate Cancer, and Survivorship

在美国，前列腺癌(PCA)是#年最常见和第二致命的癌症 男人。广泛的前列腺特异性抗原(PSA)筛查导致前列腺癌发病率增加和 诊断时的分期变化，现在90%的肿瘤在诊断时被定位。然而，确定 仅凭临床特征(PSA、临床分期和Gleason分级)识别患者的能力有限 显著增加了前列腺癌特异性死亡的风险。更好地了解致死性前列腺癌的生物学和 迫切需要识别侵袭性疾病的新标记物，以开发有效的治疗和 预防策略。在许多临床病例中，超重一直与PSA复发有关 但它在PCa患者的特异性和总死亡率中的作用仍不清楚。我们的耐人寻味 体重指数(BMI)、C-肽(胰岛素产生的标志物)和 脂联素与致死性前列腺癌支持胰岛素/胰岛素样生长因子(IGF)轴在通路中的重要作用 将能量平衡和肥胖与癌症进展和生存联系起来。在此应用程序中，我们计划 将这项激动人心的工作扩展到全面评估能量因素和PCA特定和所有原因 被诊断患有前列腺癌的男性的死亡率，占了相互竞争的死因。这些因素包括 肥胖(BMI、腰围和臀围，以及体重增加)和2型糖尿病(目标1)，生物标记物(C肽， 胰岛素、胰岛素原、胰岛素原/胰岛素比率、IGF-1、IGF结合蛋白-3和脂联素；目标2)，以及 与β细胞功能、胰岛素产生、胰岛素敏感性和肥胖相关的遗传变异 已发表的全基因组关联研究(GWAS)(目标3)。膳食胰岛素需求量(用C肽评估 得分、胰岛素指数和胰岛素负荷；目标4)、剧烈的体力活动和 邻里建成环境(按县域蔓延指数评价，目标5)。这个具有成本效益的项目使用 一位独特且特征良好的美国男性医生组成的前列腺癌患者队列，并获得了30年的完整随访 用于癌症前和癌症后暴露的结果和评估。这些研究的结果将 为能量代谢在前列腺癌进展中的作用提供新的见解，指导新的 癌症治疗目标，并帮助制定癌症预防战略，从城市规划到 饮食和生活方式的改变。

In the United States, prostate cancer (PCa) is the most commonly diagnosed and second-most lethal cancer in men. Widespread prostate-specific antigen (PSA) screening has led to an increase in PCa incidence and a shift in stage at diagnosis with 90% of tumors now being localized at diagnosis. However, the determination of clinical features (PSA, clinical stage, and Gleason grade) alone has limited ability to identify patients at substantially elevated risk of PCa-specific mortality. A better understanding ofthe biology of lethal PCa and identification of novel markers of aggressive disease are urgently needed to develop effective therapeutic and preventive strategies. Excess body weight is consistently linked to PSA recurrence in numerous clinical studies, but its role in PCa-specific and total mortality in PCa patients remains unclear. Our intriguing preliminary findings on the relations of body mass index (BMI), C-peptide (a marker of insulin production), and adiponectin with fatal PCa support important roles of insulin/insulin-like growth factor (IGF) axis in pathways connecting energy balance and obesity to cancer progression and survival. In this application, we plan to extend this exciting work to comprehensively evaluate energetic factors and PCa-specific and all-cause mortality in men diagnosed with PCa, accounting for competing causes of death. These factors include adiposity (BMI, waist and hip circumference, and weight gain) and Type 2 diabetes (Aim 1), biomarkers (Cpeptide, insulin, proinsulin, proinsulin/insulin ratio, IGF-1, IGF binding protein-3, and adiponectin; Aim 2), and genetic variants related to beta-cell function, insulin production, insulin sensitivity, and obesity identified by published genome-wide association studies (GWAS) (Aim 3). dietary insulin demand (assessed by the Cpeptide score, insulin index, and insulin load; Aim 4), vigorous physical activity and the macro-level factor of neighborhood built environment (assessed by the county sprawl index, Aim 5). This cost-effective project uses a unique and well-characterized PCa patient cohort of U.S. male physicians with 30 years of complete followup for outcomes and assessment of both pre- and post-cancer exposures. Findings of these studies will provide new insights for the role of energy metabolism in PCa progression, guide the identification of novel cancer therapeutic targets, and aid in the development of cancer prevention strategies from urban planning to diet and lifestyle modification.