Novel dietary interventions for reducing obesity-associated breast cancer

减少肥胖相关乳腺癌的新型饮食干预措施

• 批准号: 10544502
• 负责人: VICTORIA A CATENACCI
• 金额: $ 61.66万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544502
• 关键词: Acceleration; Adherence; Adipocytes; Adult; Adverse effects; Affect; Age; Antiestrogen Therapy; Attention; Attenuated; Behavior Therapy; Behavioral; Biological; Biological Markers; Body Weight decreased; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Cancer survivor; Caloric Restriction; Cancer Control; Cells; Cessation of life; Characteristics; Clinical; Clinical Research; Data; Development; Dietary Intervention; Disease; Disease susceptibility; Estrogen receptor positive; Estrogens; Extracellular Matrix; Face; Fibroblasts; Foundations; Future; Growth; Health; Health Benefit; Human; Immune; Incidence; Individual; Inflammatory; Intermittent fasting; Intervention; Intervention Studies; Intervention Trial; Lead; Life Style; Malignant Neoplasms; Mammary Neoplasms; Mediator; Medical Oncology; Menopausal Status; Metabolic; Metabolic Diseases; Metabolic dysfunction; Modality; Modeling; Neoplasm Metastasis; Newly Diagnosed; Obesity; Outcome; Overweight; Patient-Focused Outcomes; Patient-derived xenograft models of breast cancer; Patients; Persons; Phase; Play; Postmenopause; Predisposition; Premenopause; Prognosis; Protein Secretion; Quality of life; Randomized; Research Personnel; Resistance development; Risk; Role; Science; Specific qualifier value; Stromal Cells; Structure; Thinness; Time; Time-restricted feeding; Translating; Tumor Promotion; Tumor Subtype; Weight; Woman; Work; breast cancer diagnosis; breast cancer progression; cancer risk; cancer subtypes; circulating biomarkers; clinically relevant; common treatment; dietary; efficacy trial; epidemiology study; hormone therapy; improved; improved outcome; innovation; interdisciplinary collaboration; intervention delivery; intervention refinement; malignant breast neoplasm; mammary; novel; novel therapeutic intervention; nutrition; obesity treatment; patient derived xenograft model; patient population; preclinical study; therapy outcome; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumor progression; weight loss intervention

PROJECT SUMMARY Despite new treatment modalities, the incidence of breast cancer has remained steady in recent years with >250,000 new diagnoses and >40,000 deaths annually in the US. Concurrently, the proportion of US women with overweight or obesity continues to rise, and is approaching 70%. Obesity and metabolic disease (which occurs in lean and obese women) increase breast cancer incidence and worsen patient outcomes in women of all ages. Premenopausal women with obesity are at increased risk of triple negative (TN) breast cancer (lacking any targetable factors). Postmenopausal women with obesity incur more estrogen receptor (ER) positive breast cancer and are more likely to develop resistance to endocrine therapies. While estrogen is clearly an important part of this relationship, two key observations suggest that there may be estrogen-independent mechanisms at play: 1) obesity is accompanied by worse prognosis for estrogen-independent triple negative breast cancer; and 2) anti-estrogen therapies are less effective against ER+ breast tumors in women with obesity. Regardless of tumor subtype and menopausal status, excess weight is associated with poor outcomes for breast cancer patients. Weight loss is known to improve breast cancer outcomes, but most people cannot sustain the standard dietary weight loss strategies and weight regain is common. Intermittent energy restriction (IER) is a novel dietary weight loss strategy that may have more beneficial effects on metabolic health and on breast cancer risk and tumor progression. The work in this proposal will employ preclinical, clinical, and interventional studies, to examine a novel mechanism of obesity-associated tumor progression and the value and feasibility of innovative dietary interventions for eliminating obesity’s adverse effects on breast cancer. We have merged expertise in nutrition, obesity, and medical oncology to: 1) examine a novel role that cancer- associated fibroblasts (CAFs) and the tumor microenvironment (TME) may be playing in obesity-associated tumor progression; 2) investigate if the novel dietary weight loss strategy of IER can eliminate obesity-associated tumor progression; and 3) perform an ORBIT Phase IIa proof-of-concept study examining the ability of an IER- based weight loss intervention to reach meaningful clinical milestones in breast cancer patients afflicted with overweight and obesity and refine the intervention for delivery in a future randomized efficacy trial. If the objectives of this proposal are achieved, we will have: * Advanced our understanding of the obesity – breast cancer relationship, with evidence of a novel role for CAFs and the TME in obesity-associated tumor promotion for TN and ER+ breast cancer; * Established the foundation for IER weight loss trials in breast cancer survivors, with data that will help us adapt these strategies to the unique characteristics and needs of this patient population; and * Identified novel circulating biomarkers of a pro-metastatic TME, which may help identify patients most susceptible to metastatic disease.

项目概要 尽管出现了新的治疗方式，但近年来乳腺癌的发病率仍保持稳定 与此同时，美国每年新增确诊病例超过 25 万例，死亡病例超过 4 万例。 超重或肥胖的人数持续上升，并且接近70%是肥胖和代谢性疾病（其中。 发生在瘦和肥胖的女性中）会增加乳腺癌的发病率并恶化女性的患者预后 所有年龄段的绝经前肥胖女性患三阴性（TN）乳腺癌（缺乏）的风险都会增加。 绝经后肥胖女性的乳房雌激素受体（ER）阳性率更高 癌症并且更有可能对内分泌治疗产生耐药性，而雌激素显然是一个重要的因素。 作为这种关系的一部分，两个关键观察结果表明，在 发挥：1）肥胖伴随着雌激素非依赖性三阴性乳腺癌的较差预后； 2) 无论如何，抗雌激素疗法对肥胖女性的 ER+ 乳腺肿瘤效果较差。 肿瘤亚型和绝经状态，体重过重与乳腺癌的不良预后相关 众所周知，减肥可以改善乳腺癌的预后，但大多数人无法维持这个标准。 饮食减肥策略和体重反弹很常见，间歇性能量限制（IER）是一种新型饮食。 减肥策略可能对代谢健康和乳腺癌风险产生更有益的影响 该提案中的工作将采用临床前、临床和介入研究来研究肿瘤进展。 研究肥胖相关肿瘤进展的新机制以及创新的价值和可行性 消除肥胖对乳腺癌不利影响的饮食干预。 我们融合了营养、肥胖和肿瘤医学方面的专业知识，以：1）研究癌症的新作用—— 相关成纤维细胞（CAF）和肿瘤微环境（TME）可能在肥胖相关性中发挥作用 2）研究IER的新型饮食减肥策略是否可以消除与肥胖相关的因素 肿瘤进展；3) 进行 ORBIT IIa 期概念验证研究，检查 IER- 基于减肥干预的乳腺癌患者达到有意义的临床里程碑 超重和肥胖，并在未来的随机疗效试验中完善干预措施。 如果该提案的目标得以实现，我们将： * 增进了我们对肥胖与乳腺癌关系的理解，有证据表明肥胖具有新的作用 CAF 和 TME 在 TN 和 ER+ 乳腺癌中与肥胖相关的肿瘤促进作用； * 为乳腺癌幸存者的 IER 减肥试验奠定了基础，数据将帮助我们 使这些策略适应该患者群体的独特特征和需求；以及 * 确定了促转移 TME 的新型循环生物标志物，这可能最有助于识别患者 易患转移性疾病。