Leveraging Novel Randomized Clinical Trials of Vitamin D Supplementation in Patients with Colorectal Cancer: Impact on Survival and Anti-Tumor Immunity

利用维生素 D 补充剂治疗结直肠癌患者的新型随机临床试验：对生存和抗肿瘤免疫的影响

• 批准号: 10661791
• 负责人: Kimmie Ng
• 金额: $ 50.02万
• 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 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661791
• 关键词: 25-hydroxyvitamin D; Address; Antineoplastic Agents; Award; Biological; Biology; Body mass index; C26 tumor; CD3 Antigens; CYP27B1 gene; Cancer Etiology; Cell Communication; Cell Differentiation process; Cells; Cessation of life; Cholecalciferol; Collaborations; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Combined Modality Therapy; Coupled; Data; Disease; Dose; Epidemiology; Flow Cytometry; Funding; Gene Activation; Gene Expression Profiling; Genetic Transcription; Human; Immune; Immune checkpoint inhibitor; Immunity; Immunofluorescence Immunologic; Immunotherapeutic agent; Immunotherapy; Individual; Interdisciplinary Study; KRAS2 gene; Link; Malignant Neoplasms; Metastatic Neoplasm to the Liver; Microsatellite Repeats; Mixed Function Oxygenases; Neoplasm Metastasis; Oncogenes; Patient-Focused Outcomes; Patients; Phase; Placebos; Plasma; Primary Neoplasm; Prognosis; Progression-Free Survivals; Public Health; Publishing; Repression; Research; Resectable; Resistance; Risk; Role; Technology; Testing; Tumor Immunity; Tumor-infiltrating immune cells; United States; Vitamin D; Vitamin D supplementation; Vitamin D3 Receptor; Work; chemotherapy; clinical efficacy; cohort; colon cancer patients; colorectal cancer risk; cytotoxic CD8 T cells; editorial; effective therapy; epidemiologic data; immunoregulation; improved; metastatic colorectal; migration; mortality; mouse model; neoplastic cell; novel; novel therapeutic intervention; participant enrollment; phase III trial; phase change; pre-clinical; preclinical trial; predictive marker; programs; randomized, clinical trials; receptor-mediated signaling; response; single-cell RNA sequencing; standard of care; supervised learning; transcriptomic profiling; treatment strategy; tumor; tumor microenvironment; tumor-immune system interactions

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 mechanisms 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, possibly through activation of anti-tumor immunity. We will test this hypothesis within two novel randomized clinical trials (RCTs) of vitamin D supplementation: a) SOLARIS, the first phase III RCT of high- vs. low-dose vitamin D3 in combination with chemotherapy in patients with met- astatic CRC (mCRC) that was borne directly out of the SUNSHINE phase II RCT that we completed during the current funding period; and b) RCT of preoperative high-dose vitamin D3 vs. placebo in patients with resectable liver metastases for examination of vitamin D biology in these tumors, which harbor a particularly immunosup- pressive tumor microenvironment (TME) and account for a significant proportion of deaths from CRC. We will also conduct a preclinical trial of vitamin D +/- immune checkpoint inhibitors (ICIs) in a novel mouse model of CRC liver metastasis to explore whether vitamin D can overcome resistance to immunotherapy. In Aim 1, we will investigate the impact of supplemental vitamin D on plasma 25(OH)D levels and progression-free survival (PFS) among mCRC patients enrolled in the SOLARIS phase III RCT, and explore predictive biomarkers of clinical efficacy. In Aim 2, we will investigate the impact of supplemental vitamin D on the TME of primary colon tumors and liver metastases in patients enrolled on the preoperative vitamin D RCT using spatial transcriptional profiling and multiplex immunofluorescence. In Aim 3, we will investigate the impact of supplemental vitamin D +/- ICIs on tumor response and anti-tumor immunity in mouse models of microsatellite stable (MSS) CRC with and without liver metastases using multiparameter flow cytometry and single-cell RNA sequencing. In summary, this translational proposal leverages unprecedented RCTs of vitamin D, cutting-edge technologies, and multidis- ciplinary collaborations to extend our previous work and take the next critical steps in understanding vitamin D in CRC. Our findings will lead to incorporation of vitamin D into standard of care and inform new combination strategies with immunotherapy, which has thus far been ineffective in MSS CRC. Importantly, the global impact of an inexpensive and safe therapy such as vitamin D cannot be underestimated for improving the prognosis of this lethal disease.

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（CRC）的风险较低 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， 这些发现是否反映了真正的因果关系，以及这些发现的生物学机制是什么。 维生素D的活性。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可能通过激活抗肿瘤免疫力，改善CRC患者的生存率。我们将 在两项关于维生素D补充剂的新型随机临床试验（RCT）中检验这一假设：a）SOLARIS， 第一个III期随机对照试验（RCT），在患有甲硫氨酸血症的患者中比较高剂量与低剂量维生素D3联合化疗， 无定向性CRC（mCRC），直接来自我们在2008年完成的SUNSHINE II期RCT。 当前资助期;和B）可切除肿瘤患者术前高剂量维生素D3对比安慰剂的RCT 肝转移，用于检查这些肿瘤中的维生素D生物学，这些肿瘤具有特别的免疫抑制作用， 肿瘤微环境（TME）的压力，并占CRC死亡的显着比例。我们将 还在一种新的小鼠模型中进行了维生素D +/-免疫检查点抑制剂（ICI）的临床前试验， CRC肝转移，探讨维生素D是否可以克服免疫治疗的抵抗。目标1： 将研究补充维生素D对血浆25（OH）D水平和无进展生存期的影响 (PFS)在SOLARIS III期RCT中招募的mCRC患者中，并探索 临床疗效在目标2中，我们将研究补充维生素D对原发性结肠TME的影响 使用空间转录技术在术前维生素D RCT中登记的患者中的肿瘤和肝转移 分析和多重免疫荧光。在目标3中，我们将研究补充维生素D的影响 +/-ICI对微卫星稳定（MSS）CRC小鼠模型中肿瘤应答和抗肿瘤免疫的影响， 并且使用多参数流式细胞术和单细胞RNA测序没有肝转移。总的来说， 这一转化提案利用了前所未有的维生素D RCT、尖端技术和多学科， ciplinary合作，以扩大我们以前的工作，并采取下一步的关键步骤，了解维生素D 在《儿童权利公约》。我们的研究结果将导致将维生素D纳入标准护理，并为新的组合提供信息。 免疫治疗策略，迄今为止在MSS CRC中无效。重要的是，全球影响 一种廉价而安全的治疗方法，如维生素D，在改善预后方面不可低估。 这种致命的疾病。

项目成果

NGS-based identification and tracing of microsatellite instability from minute amounts DNA using inter-Alu-PCR.

• DOI: 10.1093/nar/gkaa1175
• 发表时间: 2021-02-26
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Yu F;Leong KW;Makrigiorgos A;Adalsteinsson VA;Ladas I;Ng K;Mamon H;Makrigiorgos GM
• 通讯作者: Makrigiorgos GM

Effect of Exercise or Metformin on Biomarkers of Inflammation in Breast and Colorectal Cancer: A Randomized Trial.

• DOI: 10.1158/1940-6207.capr-20-0188
• 发表时间: 2020-12
• 期刊: Cancer prevention research (Philadelphia, Pa.)
• 作者: Brown JC;Zhang S;Ligibel JA;Irwin ML;Jones LW;Campbell N;Pollak MN;Sorrentino A;Cartmel B;Harrigan M;Tolaney SM;Winer EP;Ng K;Abrams TA;Sanft T;Douglas PS;Hu FB;Fuchs CS;Meyerhardt JA
• 通讯作者: Meyerhardt JA

Can an apple a day keep cancer away?

每天一个苹果能远离癌症吗？

• DOI: 10.1093/ajcn/nqab133
• 发表时间: 2021
• 期刊: The American journal of clinical nutrition
• 作者: Yuan,Chen;Ng,Kimmie
• 通讯作者: Ng,Kimmie