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: 9900749
• 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 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900749
• 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; 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; outcome forecast; 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.

项目总结/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， 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)并提高了CRC的生存率。尽管有令人信服的证据表明维生素D与CRC有关， 问题仍然是这些发现是否反映了真正的因果关系，以及生物机制是什么， 维生素D活性的差异。我们的中心假设是，补充维生素D，以达到足够的 25（OH）D水平导致CRC患者生存率提高，并影响几种肿瘤途径， 可以作为有效性的生物标志物和新治疗策略的靶点。我们要测试这个皮下组织- 在两个新维生素D补充剂的随机临床试验中进行：a）II期双盲随机试验， 高剂量与低剂量维生素D3联合化疗治疗转移性乳腺癌的对照研究 B）术前高剂量维生素D3与安慰剂在CRC患者中的随机试验， 可切除的结肠癌，用于在新鲜人肿瘤组织中检查维生素D生物学。我们也会撬- 在一项已完成的NCI申办的III期试验中招募了大量转移性CRC患者的前瞻性队列 化疗（CALGB/SWOG 80405），以进一步定义和验证维生素D作用的生物标志物。在Aim中 1，我们将确定补充维生素D对CRC患者生存的影响， 关于维生素D剂量-反应关系，并探索维生素D状态，反应和 功效我们将研究循环中维生素D结合蛋白的水平和肿瘤中维生素D结合蛋白的表达， 维生素D受体、1α-羟化酶和24-羟化酶与我们范围内的生存率提高相关， domized试验，以及这些标志物是否改变维生素D和患者结果之间的关系。在 目的2，我们将进行维生素D的精确医学分析，以阐明其抗- CRC中的肿瘤活性。我们将探讨维生素D补充剂对炎症的肿瘤标志物的影响， 淋巴细胞浸润和炎性基因标记， 术前接受高剂量维生素D3治疗的患者与安慰剂治疗的患者。我们还将执行下一代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Nanostring分析，以识别 fy与维生素D介导的致癌作用相关的独特遗传和转录特征。总括而言─ 玛丽，这一翻译建议利用创新的维生素D随机试验，采取下一个关键 了解CRC中维生素D活性和生物学的步骤。我们的发现将证实因果关系，提供新的 深入了解维生素D活性的生物标志物，并将维生素D纳入标准治疗 - 包括免疫治疗-最终目标是提高CRC患者的生存率。