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

点击翻译按钮获取中文摘要

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.