Deaths from lung cancer are the highest of all cancers in North America and elsewhere and, because of the long incubation time, are likely to remain so for the foreseeable future. Furthermore, although the 5-year survival rate of stage I lung cancer is 60-70%, later stage disease has a very poor prognosis. Accurate detection of asymptomatic early stage lung cancer in individuals at risk is currently unreliable. A better understanding of the basic biochemistry of lung cancers is a prerequisite to mechanism-based reliable early detection of the disease, and to improved approaches to treatment. The very complexity of the transformed cells, and the variable host-tumor interactions, makes the problem refractory to any single approach. A systems biochemistry approach in which lung cancers are studied at the mechanistic level in the laboratory, in mouse models and in human subjects offers the opportunity to address the complexity of cancer development and progression. The use of stable isotope resolved metabolomics provides the necessary direct biochemical information about lung cancer with minimal processing that is not otherwise available. This program will address the problem in a 3-pronged approach, based on the following integrated projects: Project 1: Cellular Systems Biochemistry. Microenvironmental nutrient availability and immune modulation in lung cancer cells. Project 2;Preclinical Systems Biochemistry. Using SIRM in Human NSCLC xenograft mouse to determine biochemical mechanisms of immunomodulator B-glucan. Project 3: Translational Systems Biochemistry. Molecular mechanisms of NSCLC and response to B-glucan by SIRM. The three projects will use a common mechanistic approach to understanding cancer biochemistry namely stable isotope resolved metabolomics (SIRM) that we have been developing over the last eight years. The analytical requirements will be met in the SIRM Analytical Core, which also supplies the necessary sample handling and bioinformatics support for the three projects. Core A provides overall administrative support.

Public Health Relevance

Deaths from lung cancer are the highest among all cancers in North America and cure rates remain low. We seek to gain a deeper understanding of lung cancer biochemistry using a novel approach we developed. Improved knowledge will have direct impact on early diagnosis and prognosis. The biochemical differences between lung cancer subtypes can be related to appropriate treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA163223-01A1
Application #
8415060
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (O1))
Program Officer
Spalholz, Barbara A
Project Start
2013-03-01
Project End
2018-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$1,427,718
Indirect Cost
$475,906
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Fan, Teresa W-M; Warmoes, Marc O; Sun, Qiushi et al. (2016) Distinctly perturbed metabolic networks underlie differential tumor tissue damages induced by immune modulator β-glucan in a two-case ex vivo non-small-cell lung cancer study. Cold Spring Harb Mol Case Stud 2:a000893
Albeituni, Sabrin H; Ding, Chuanlin; Liu, Min et al. (2016) Yeast-Derived Particulate β-Glucan Treatment Subverts the Suppression of Myeloid-Derived Suppressor Cells (MDSC) by Inducing Polymorphonuclear MDSC Apoptosis and Monocytic MDSC Differentiation to APC in Cancer. J Immunol 196:2167-80
Li, Jing; Song, Jun; Zaytseva, Yekaterina Y et al. (2016) An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature 533:411-5
Lane, Andrew N; Higashi, Richard M; Fan, Teresa W-M (2016) Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM). Metabolomics 12:
Krem, Maxwell M; Yan, Jun (2016) To b(ortezomib) or not to be: the stroma's the thing. J Pathol 240:123-5
Fan, Teresa W-M; Lane, Andrew N (2016) Applications of NMR spectroscopy to systems biochemistry. Prog Nucl Magn Reson Spectrosc 92-93:18-53
Fan, Teresa W-M; Lane, Andrew N; Higashi, Richard M (2016) Stable Isotope Resolved Metabolomics Studies in Ex Vivo TIssue Slices. Bio Protoc 6:
Lane, Andrew N; Arumugam, Sengodagounder; Lorkiewicz, Pawel K et al. (2015) Chemoselective detection and discrimination of carbonyl-containing compounds in metabolite mixtures by 1H-detected 15N nuclear magnetic resonance. Magn Reson Chem 53:337-43
Liu, Min; Luo, Fengling; Ding, Chuanlin et al. (2015) Dectin-1 Activation by a Natural Product β-Glucan Converts Immunosuppressive Macrophages into an M1-like Phenotype. J Immunol 195:5055-65
Tarrado-Castellarnau, Míriam; Cortés, Roldán; Zanuy, Miriam et al. (2015) Methylseleninic acid promotes antitumour effects via nuclear FOXO3a translocation through Akt inhibition. Pharmacol Res 102:218-34

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