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 ?-glucan. Project 3: Translational Systems Biochemistry. Molecular mechanisms of NSCLC and response to ?-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 #
7P01CA163223-02
Application #
8616357
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (O1))
Program Officer
Spalholz, Barbara A
Project Start
2014-08-19
Project End
2018-02-28
Budget Start
2014-08-19
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$1,236,441
Indirect Cost
$313,183
Name
University of Kentucky
Department
None
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Higashi, Richard M; Fan, Teresa W-M; Lorkiewicz, Pawel K et al. (2014) Stable isotope-labeled tracers for metabolic pathway elucidation by GC-MS and FT-MS. Methods Mol Biol 1198:147-67
Wu, Pin; Wu, Dang; Ni, Chao et al. (2014) ??T17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity 40:785-800
Xie, Han; Hanai, Jun-Ichi; Ren, Jian-Guo et al. (2014) Targeting lactate dehydrogenase--a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metab 19:795-809