The studies proposed in this new SPORE project are designed to provide strong rationale for a vitamin D3- based approach to lung cancer prevention. We recently demonstrated that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin 03, significantly inhibits the growth of lung cancer cells and antagonizes nuclear factor-KB (NF-KB) action. NF-KB signaling plays a key role in inflammation, and has been shown to underlie smoking-associated lung inflammation and carcinogenesis. Together, this suggests that 1,25(OH)2D3 may be useful for chemoprevention of lung cancer. Because systemic 1,25(OH)2D3 administration is complicated by its hypercalcemia-inducing properties, we propose to use oral supplementation with vitamin D3 to safely achieve chemopreventive1,25(OH)2D3 levels within lung tissues. Upon ingestion, vitamin D3 is readily converted to the non-toxic circulating precursor, 25(OH)D3, which is subsequently converted to 1,25(OH)2D3 within the lung by CYP27B1-expressing bronchial epithelial cells and alveolar macrophages. To determine the impact of vitamin D3 exposure on pulmonary inflammation and lung cancer risk we will:
(Aim 1) utilize samples and data from 548 cases from our SPORE Lung Tumor Registry, and 180 cases and 993 controls from the Pittsburgh Lung Screening Study (PLuSS) to evaluate the relationship between variation in vitamin D3 and NF-KB pathway genes, 25(OH)D3 serum levels, and risk of lung cancer;
(Aim 2) use banked samples from 150 PLuSS participants to establish the association between 25(OH)D3 serum levels and inflammation and lung cancer risk biomarkers in sputum;
(Aim 3) use murine models to quantify the effects of vitamin D3 status on NNK-induced lung carcinogenesis and cigarette smoke-induced pulmonary inflammation, and examine the impact of cigarette smoke exposure on 25(OH)D3 levels and expression of vitamin D3-metabolizing enzymes;and, (Aim 4) conduct a bioeffectiveness study of vitamin D3 supplementation in individuals at increased risk for lung cancer. We will evaluate whether supplementation corrects vitamin D3 deficiency and also investigate effects on inflammation and lung cancer risk biomarkers in sputum, circulating inflammation markers, and pulmonary function in this aim.
Despite the recognized need, there are currently no drugs or dietary supplements approved for the prevention of lung cancer. This project seeks to change this. By providing mechanistic rationale for oral vitamin D3 supplementation and evidence of its anti-tumor efficacy and safety, the proposed studies are expected to support the design and conduct of a Phase II lung cancer chemoprevention trial.
|Leng, Shuguang; Diergaarde, Brenda; Picchi, Maria A et al. (2018) Gene Promoter Hypermethylation Detected in Sputum Predicts FEV1 Decline and All-Cause Mortality in Smokers. Am J Respir Crit Care Med 198:187-196|
|Rothenberger, Natalie J; Somasundaram, Ashwin; Stabile, Laura P (2018) The Role of the Estrogen Pathway in the Tumor Microenvironment. Int J Mol Sci 19:|
|Yochum, Zachary A; Cades, Jessica; Wang, Hailun et al. (2018) Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene :|
|Stabile, Laura P; Farooqui, Mariya; Kanterewicz, Beatriz et al. (2018) Preclinical Evidence for Combined Use of Aromatase Inhibitors and NSAIDs as Preventive Agents of Tobacco-Induced Lung Cancer. J Thorac Oncol 13:399-412|
|Volonte, Daniela; Vyas, Avani R; Chen, Chen et al. (2018) Caveolin-1 promotes the tumor suppressor properties of oncogene-induced cellular senescence. J Biol Chem 293:1794-1809|
|Hopkins, Kathleen G; Ferson, Peter F; Shende, Manisha R et al. (2017) Prospective study of quality of life after lung cancer resection. Ann Transl Med 5:204|
|Vendetti, Frank P; Leibowitz, Brian J; Barnes, Jennifer et al. (2017) Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation. Sci Rep 7:41892|
|Tarhini, Ahmad A; Rafique, Imran; Floros, Theofanis et al. (2017) Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non-small cell lung cancer. Cancer 123:2936-2944|
|Sun, Fan; Xiao, Gutian; Qu, Zhaoxia (2017) Isolation of Murine Alveolar Type II Epithelial Cells. Bio Protoc 7:|
|Dandachi, Nadine; Kelly, Neil J; Wood, John P et al. (2017) Macrophage Elastase Induces TRAIL-mediated Tumor Cell Death through Its Carboxy-Terminal Domain. Am J Respir Crit Care Med 196:353-363|
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