Increased eicosanoid production has been associated with many types of cancer including lung cancer.Inhibition of cyclooxygenase (COX, PGH2 synthase) activity decreases eicosanoid production and preventslung cancer in animal models. Prostacyclin I2 (PGI2) is a PGH2 metabolite with anti-inflammatory, antiproliferative,and potent anti-metastatic properties. Our laboratory has shown that targeted overexpressionof PGI2 synthase (PGIS) or chemoprevention with the PGI2 analog lloprost significantly reduced lung tumormultiplicity and incidence in mice, suggesting that manipulation of the arachidonic acid pathway downstreamfrom COX is a target for the prevention of lung cancer. These studies resulted in the initiation of achemoprevention trial in which patients at risk for lung cancer are treated with lloprost. Studies performedduring the previous funding period have shown that the anti-tumorigenic effects of PGI2 are not mediatedthrough the cell-surface receptor, but instead via activation of the peroxisome proliferator-activated receptorpathway, specifically PPAR^. Recent retrospective studies indicate that thiozolidinediones such asrosiglitazone, which are specific PPARy activators, reduce the risk of lung cancer. We have shown thatPPARy-transgenic mice are protected against lung tumorigenesis. In human NSCLC, PPARy activationinhibits anchorage-independent growth and invasiveness, and promotes differentiation. These effects areassociated with inhibition of COX-2 and decreases in cytokine production. While PGI2 and its analogsactivate PPARy in non-transformed epithelial cells, this ability is lost in many NSCLC lines. We have recentlydemonstrated that the inability of PGI2 to engage PPARy in NSCLC is correlated with the loss of signalingthrough Wnt7a and its cognate receptor Fzd9. The goal of the current proposal is to examine the role of PGI2and PPARy in the development of lung tumors. Studies will use in vitro studies and mouse models to definemolecular effectors and markers of response. These findings will be applied to analysis of human samplesfrom the lloprost trial and a new Rosiglitazone chemoprevention trial, as well as samples from human lungcancers.
Three specific aims are proposed.
Aim 1 will use in vitro approaches to define biomarkers oflloprost and Rosiglitazone sensitivity in a panel of NSCLC, and to examine interactions between theseagents and EGFR-TKIs.
Aim 2 will use a chemical carcinogenesis model to examine the combinatorialeffects of lloprost and rosiglitazone and erlotinib. Xenografts of human NSCLC will be used to establish theinteractions between lloprost and Fzd9.
Aim 3 will examine expression of molecules in this pathway insamples from chemoprevention trials and correlate changes with alterations in the degree of dysplasia andresponse to lloprost or Rosiglitazone. Expression of molecules in this pathway will be examined in humantumors using tissue microarrays. These studies will establish the role of this pathway in lung cancer initiationand progression, and help define new therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA058187-14
Application #
7448824
Study Section
Special Emphasis Panel (ZCA1-GRB-I (J1))
Project Start
2008-05-01
Project End
2013-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
14
Fiscal Year
2008
Total Cost
$193,606
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Tippimanchai, Darinee D; Nolan, Kyle; Poczobutt, Joanna et al. (2018) Adenoviral vectors transduce alveolar macrophages in lung cancer models. Oncoimmunology 7:e1438105
DeHart, David N; Lemasters, John J; Maldonado, Eduardo N (2018) Erastin-Like Anti-Warburg Agents Prevent Mitochondrial Depolarization Induced by Free Tubulin and Decrease Lactate Formation in Cancer Cells. SLAS Discov 23:23-33
Ren, Shengxiang; Zhang, Shucai; Jiang, Tao et al. (2018) Early detection of lung cancer by using an autoantibody panel in Chinese population. Oncoimmunology 7:e1384108
Davies, Kurtis D; Le, Anh T; Sheren, Jamie et al. (2018) Comparison of Molecular Testing Modalities for Detection of ROS1 Rearrangements in a Cohort of Positive Patient Samples. J Thorac Oncol 13:1474-1482
Iams, Wade T; Yu, Hui; Shyr, Yu et al. (2018) First-line Chemotherapy Responsiveness and Patterns of Metastatic Spread Identify Clinical Syndromes Present Within Advanced KRAS Mutant Non-Small-cell Lung Cancer With Different Prognostic Significance. Clin Lung Cancer 19:531-543
McDaniel, Nellie K; Cummings, Christopher T; Iida, Mari et al. (2018) MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents. Mol Cancer Ther 17:2297-2308
Ghosh, Moumita; Miller, York E; Vandivier, R William et al. (2018) Reply to Sohal: Airway Basal Cell Reprogramming and Epithelial-Mesenchymal Transition: A Potential Key to Understanding Early Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 197:1645-1646
Ghosh, Moumita; Miller, York E; Nakachi, Ichiro et al. (2018) Exhaustion of Airway Basal Progenitor Cells in Early and Established Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 197:885-896
Farago, Anna F; Taylor, Martin S; Doebele, Robert C et al. (2018) Clinicopathologic Features of Non-Small-Cell Lung Cancer Harboring an NTRK Gene Fusion. JCO Precis Oncol 2018:
He, Yayi; Liu, Sangtian; Mattei, Jane et al. (2018) The combination of anti-KIR monoclonal antibodies with anti-PD-1/PD-L1 monoclonal antibodies could be a critical breakthrough in overcoming tumor immune escape in NSCLC. Drug Des Devel Ther 12:981-986

Showing the most recent 10 out of 435 publications