Epidemiologic and laboratory studies implicate Vitamin D (VitD) in both reducing the risk of developing colorectal cancer (CRC) and improving survival among patients with established CRC. VitD complexes with the intracellular VitD receptor (VDR) to regulate target genes, but the mechanisms behind the significant influence on CRC development and progression are unknown. Moreover, no study has adequately examined the impact of pharmacologic VitD supplementation on outcome in patients with CRC. During the last funding period our dose-finding study of VitD supplementation in African Americans determined that 4000 lU of VitD3 daily is required to raise plasma VitD levels into the optimal range associated with cancer prevention. In this continuation project, we propose a cohesive laboratory and clinical effort using cell lines, mouse models, and human patients to define the mechanism and basis of VitD and VDR action in CRC biology, to address causality, and to assess the role of VitD supplementation on CRC patient outcomes in a randomized intervention trial.
In Aim 1 we will use genetically engineered mice to test the hypothesis that VitD suppresses CRC development and progression through direct actions on intestinal mucosal cells. We will use chromatin immunoprecipitation and massively parallel sequencing (ChlP-seq) to identify VitD-VDR transcriptional targets in CRC cell lines and in human colon cancers and metastases collected in an innovative preoperative trial of VitD supplementation. We will apply innovative computational tools to identify bona fide targets and key VitD-dependent pathways. Comparisons of VDR occupancy profiles in normal and cancerous colon in the same individual, and between VitD- or placebo-treated tumors, will deliver a refined understanding of target genes relevant to CRC, allowing rapid translation of in vitro findings to the clinic. The cornerstone of Aim 2 is a prospective, randomized, double-blind phase II clinical trial to test the hypothesis that, in conjunction with standard chemotherapy, pharmacologic doses of VitD3 improve progression-free survival in patients with metastatic CRC. We will use powerful information from Aim 1 on VitD-VDR genomic binding sites and candidate target genes to examine their roles in differential VitD sensitivity within the clinical trial. Furthermore, we will determine whether polymorphisms in these binding sites and regulated genes are associated with greater or lesser response to VitD in CRC progression in humans, and assess whether supplemental VitD3 confers greater benefit when tumors overexpress VDR or carry wild-type KRAS. This translational project leverages multidisciplinary expertise and complementary approaches to identify molecular mechanisms, novel biomarkers, and optimal clinical strategies to integrate supplemental VitD in CRC prevention and treatment. Our findings will meaningfully advance strategies for CRC prevention and treatment, including routine monitoring of VitD status and incorporation of VitD supplementation in patient care, resulting in rapid and measurable reductions in CRC incidence and mortality.

Public Health Relevance

Knowledge of the mechanisms that underiie VitD's potent action in CRC would greatly enhance acceptance and integration of VitD into routine cancer prevention and treatment. In an era of expensive and toxic anti-cancer agents, VitD is an attractive option with respect to safety and cost. The potential to modulate cancer through nutritional factors is very real;this proposal aims to advance that goal through mechanistic studies and a clinical trial, anticipating eventual reductions in the incidence and mortality of CRC.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Special Emphasis Panel (ZCA1-RPRB-M (J1))
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Agarwal, Rajeev K
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Dana-Farber Cancer Institute
United States
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Russo, Mariangela; Siravegna, Giulia; Blaszkowsky, Lawrence S et al. (2016) Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer. Cancer Discov 6:147-53
Kim, Sun A; Inamura, Kentaro; Yamauchi, Mai et al. (2016) Loss of CDH1 (E-cadherin) expression is associated with infiltrative tumour growth and lymph node metastasis. Br J Cancer 114:199-206
Kugel, Sita; Sebastián, Carlos; Fitamant, Julien et al. (2016) SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b. Cell 165:1401-15
Delaney, Susan K; Hultner, Michael L; Jacob, Howard J et al. (2016) Toward clinical genomics in everyday medicine: perspectives and recommendations. Expert Rev Mol Diagn 16:521-32
Mima, Kosuke; Cao, Yin; Chan, Andrew T et al. (2016) Fusobacterium nucleatum in Colorectal Carcinoma Tissue According to Tumor Location. Clin Transl Gastroenterol 7:e200
Whitley, Melodi Javid; Cardona, Diana M; Lazarides, Alexander L et al. (2016) A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer. Sci Transl Med 8:320ra4
Ahronian, Leanne G; Corcoran, Ryan B (2016) Effective MAPK Inhibition is critical for therapeutic responses in colorectal cancer with BRAF mutations. Mol Cell Oncol 3:e1048405
Saha, Supriya K; Zhu, Andrew X; Fuchs, Charles S et al. (2016) Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. Oncologist 21:594-9
Ou, Wen-Bin; Lu, Minmin; Eilers, Grant et al. (2016) Co-targeting of FAK and MDM2 triggers additive anti-proliferative effects in mesothelioma via a coordinated reactivation of p53. Br J Cancer 115:1253-1263
Zeng, Chenjie; Matsuda, Koichi; Jia, Wei-Hua et al. (2016) Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk. Gastroenterology 150:1633-45

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