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

项目摘要/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， 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 (儿童权利公约)和提高儿童权利公约的存活率。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 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，这些问题仍然存在。 维生素D活性失调的原因是。我们的中心假设是，补充维生素D可以达到足够的 25(OH)D水平可改善结直肠癌患者的存活率，并影响多种肿瘤通路 可作为疗效的生物标记物和新的治疗策略的靶标。我们将测试这个假说- 维生素D补充剂的两个新的随机临床试验中的SIS：A)II期双盲随机- 大剂量维生素D3与小剂量维生素D3联合化疗治疗转移性肿瘤的对照研究 结直肠癌，以及b)术前大剂量维生素D3与安慰剂对照的随机试验 用于新鲜人类肿瘤组织中维生素D生物学检查的可切除结肠癌。我们还将杠杆- 在NCI赞助的已完成的III期试验中登记的转移性结直肠癌患者的一个丰富的预期队列 (CALGB/SWOG 80405)，以进一步定义和验证维生素D作用的生物标记物。在AIM 1、我们将确定补充维生素D对结直肠癌患者生存的影响，检验不同的假设 关于维生素D的剂量-反应关系，并探索维生素D状态、反应和 功效。我们将调查循环中维生素D结合蛋白的水平和肿瘤组织中 维生素D受体、1-α-羟基酶和24-羟基酶与提高我们的存活率有关。 受控试验，以及这些标志物是否改变了维生素D和患者预后之间的关系。在……里面 目的2、我们将对维生素D进行精确的医学分析，以阐明其抗高血压的机制。 结直肠癌的肿瘤活动性。我们将探讨补充维生素D对炎症性肿瘤标志物的影响。 炎症性结肠炎患者手术切除标本中的炎症反应、淋巴细胞浸润和炎性基因特征。 术前服用大剂量维生素D3的患者与安慰剂对照。我们还将表演下一代Se- 维生素D水平高低的结直肠癌患者肿瘤基因测序及纳米链分析 FY独特的与维生素D介导的致癌相关的遗传和转录特征。总而言之- Mary，这项转换建议利用创新的维生素D随机试验来进行下一步关键 了解结直肠癌患者维生素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，并可能将维生素D纳入标准治疗 --包括免疫治疗--最终目标是提高结直肠癌患者的存活率。

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.