Novel randomized controlled trials of vitamin D supplementation in patients with colorectal cancer: Impact on survival and biology

结直肠癌患者补充维生素 D 的新型随机对照试验：对生存和生物学的影响

• 批准号: 10113550
• 负责人: Kimmie Ng
• 金额: $ 49.4万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10113550
• 关键词: 25-hydroxyvitamin D; Address; Adopted; Affect; Age; Anti-Inflammatory Agents; Antineoplastic Agents; Award; Biological; Biological Markers; Biology; Blood specimen; CYP27B1 gene; Cancer Etiology; Cancer and Leukemia Group B; Cessation of life; Cholecalciferol; Clinical; Colectomy; Colon Carcinoma; Colorectal Cancer; Colorectal Neoplasms; DNA; Data; Dose; Double-Blind Method; Enrollment; Epidemiology; Etiology; Follow-Up Studies; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Health Occupations; Human; Immune signaling; Immunotherapy; Incidence; Individual; Inflammatory; Intervention; Investigation; Knowledge; Lead; Link; Lymphocytic Infiltrate; Mediating; Mixed Function Oxygenases; Mutation; Neoplasm Metastasis; Nurses' Health Study; Operative Surgical Procedures; Partner in relationship; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Placebos; Plasma; Prognosis; Progression-Free Survivals; Prospective cohort; Prospective cohort study; Public Health; Race; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Research; Research Personnel; Resectable; Resected; Risk; Safety; Signal Pathway; Southwest Oncology Group; Specimen; Supplementation; Testing; Tumor Markers; Tumor Tissue; Variant; Vitamin D; Vitamin D Deficiency; Vitamin D supplementation; Vitamin D-Binding Protein; Vitamin D3 Receptor; Work; biobank; cancer cell; carcinogenesis; chemotherapy; cohort; colon cancer patients; colorectal cancer risk; cost; design; effective therapy; epidemiologic data; experience; genetic signature; immunoregulation; improved; inflammatory marker; innovation; insight; metastatic colorectal; mortality; nano-string; neoplastic; next generation; novel; phase III trial; pre-clinical; precision medicine; precision oncology; racial disparity; randomized trial; response; sociodemographic group; treatment strategy; tumor

PROJECT SUMMARY / ABSTRACT Abundant preclinical and epidemiologic data suggest that vitamin D possesses anti-neoplastic activity, and that individuals with higher plasma 25-hydroxyvitamin D [25(OH)D] levels have lower risk of colorectal cancer (CRC) and improved survival from CRC. Despite compelling evidence implicating vitamin D in CRC, critical questions remain about whether these findings reflect a true causal relationship, and what the biological mech- anisms of vitamin D activity are. Our central hypothesis is that vitamin D supplementation to achieve sufficient levels of 25(OH)D leads to improved survival in CRC patients and influences several neoplastic pathways that can be exploited as biomarkers of efficacy and targets for novel treatment strategies. We will test this hypothe- sis within two novel randomized clinical trials of vitamin D supplementation: a) a phase II double-blind random- ized trial of high- versus low-dose vitamin D3 in combination with chemotherapy in patients with metastatic CRC, and b) a randomized trial of preoperative high-dose vitamin D3 versus placebo in patients with resectable colon cancer for examination of vitamin D biology in fresh human tumor tissue. We will also lever- age a rich prospective cohort of metastatic CRC patients enrolled in a completed NCI-sponsored phase III trial of chemotherapy (CALGB/SWOG 80405) to further define and validate biomarkers of vitamin D action. In Aim 1, we will determine the impact of supplemental vitamin D on survival of CRC patients, test distinct hypotheses about the vitamin D dose-response relationship, and explore biomarkers of vitamin D status, response, and efficacy. We will investigate whether circulating levels of vitamin D binding protein and tumoral expression of vitamin D receptor, 1α-hydroxylase, and 24-hydroxylase are associated with improved survival within our ran- domized trials, and whether these markers modify the relationship between vitamin D and patient outcome. In Aim 2, we will conduct a precision medicine analysis of vitamin D to elucidate the mechanistic basis for its anti- tumor activity in CRC. We will explore the impact of vitamin D supplementation on tumoral markers of inflam- mation, lymphocytic infiltrates, and inflammatory gene signatures in surgical colectomy specimens from pa- tients treated with high-dose preoperative vitamin D3 versus placebo. We will also perform next generation se- quencing and Nanostring analysis of tumors from CRC patients with high- versus low vitamin D status to identi- fy unique genetic and transcriptional signatures associated with vitamin D-mediated carcinogenesis. In sum- mary, this translational proposal leverages innovative randomized trials of vitamin D to take the next critical steps in understanding vitamin D activity and biology in CRC. Our findings will confirm causality, provide new insights into biomarkers of vitamin D activity, and lead to potential inclusion of vitamin D into standard therapy – including immunotherapy – with the ultimate goal of improving the survival of patients with CRC.

项目概要/摘要 大量的临床前和流行病学数据表明维生素 D 具有抗肿瘤活性，并且 血浆 25-羟基维生素 D [25(OH)D] 水平较高的个体患结直肠癌的风险较低 (CRC) 并提高 CRC 的生存率。尽管有令人信服的证据表明维生素 D 与结直肠癌有关，但关键 关于这些发现是否反映了真正的因果关系，以及其生物学机制是什么，仍然存在疑问。 维生素 D 活性的特征是。我们的中心假设是补充维生素 D 以达到足够的水平 25(OH)D 水平可提高 CRC 患者的生存率并影响多种肿瘤途径， 可以用作功效的生物标志物和新治疗策略的目标。我们将测试这个假设 两项关于补充维生素 D 的新颖随机临床试验中的研究：a) II 期双盲随机- 高剂量与低剂量维生素 D3 联合化疗治疗转移性患者的临床试验 CRC，以及 b) 在患有以下疾病的患者中进行的术前高剂量维生素 D3 与安慰剂的随机试验 可切除结肠癌，用于检查新鲜人类肿瘤组织中的维生素 D 生物学。我们还将杠杆—— 招募了参加已完成的 NCI 赞助的 III 期试验的丰富的转移性 CRC 患者前瞻性队列 化疗 (CALGB/SWOG 80405) 进一步定义和验证维生素 D 作用的生物标志物。瞄准 1、我们将确定补充维生素 D 对 CRC 患者生存的影响，检验不同的假设 了解维生素 D 剂量-反应关系，并探索维生素 D 状态、反应和维生素 D 的生物标志物 功效。我们将研究维生素 D 结合蛋白的循环水平和肿瘤表达是否 维生素 D 受体、1α-羟化酶和 24-羟化酶与我们体内的生存率提高有关。 局部试验，以及这些标志物是否改变维生素 D 与患者结果之间的关系。在 目标2，我们将对维生素D进行精准医学分析，以阐明其抗- CRC 中的肿瘤活性。我们将探讨补充维生素 D 对炎症肿瘤标志物的影响 结肠切除手术标本中的炎症、淋巴细胞浸润和炎症基因特征 术前接受高剂量维生素 D3 治疗的患者与安慰剂相比。我们还将进行下一代se- 对高维生素 D 状态与低维生素 D 状态的 CRC 患者的肿瘤进行测序和纳米线分析，以识别 发现与维生素 D 介导的致癌作用相关的独特遗传和转录特征。总而言之—— 玛丽，这个转化提案利用维生素 D 的创新随机试验来采取下一个关键 了解 CRC 中维生素 D 活性和生物学的步骤。我们的研究结果将证实因果关系，提供新的 深入了解维生素 D 活性的生物标志物，并有可能将维生素 D 纳入标准疗法 – 包括免疫疗法 – 最终目标是提高 CRC 患者的生存率。