Accession Number : ADA611017


Title :   Targeting Metabolic Survival Pathways in Lung Cancer via Combination Therapy


Descriptive Note : Annual rept. 1 June 2013 to 31 May 2014


Corporate Author : CALIFORNIA UNIV SAN DIEGO LA JOLLA


Personal Author(s) : Metallo, Christian


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a611017.pdf


Report Date : Jun 2014


Pagination or Media Count : 37


Abstract : This proposal aims to identify critical metabolic pathways necessary for survival of liver kinase B1 (LKB1)-deficient non-small cell lung cancer (NSCLC) cell lines. We have conducted 13C metabolic flux analysis studies in LKB1 proficient or deficient NSCLC cells under nutrient complete or metabolic stress conditions (e.g. hypoxia, matrix detachment). Using these analyses we can demonstrate that cells lacking the LKB1 tumor suppressor exhibit limited oxidation of glucose-derived pyruvate in mitochondria. LKB1-deficient cells also exhibit increased reliance on glutamine metabolism. Treatment with biguanides such as metformin or phenformin decreases oxidative mitochondrial metabolism. A critical defect we have observed in our analyses is the inability of LKB1- deficient tumor cells to recover in response to phenformin treatment, as carbohydrate oxidation remains compromised for an extended period of time after removal/washout of phenformin. Given the dependence of LKB1-deficient tumor cells on glutamine metabolism, we are targeting a critical enzyme responsible for catalyzing the entry of glutamine carbon into the Krebs cycle in mitochondria, glutaminase.


Descriptors :   *LUNG CANCER , CELLS(BIOLOGY) , GLUTAMINE , METABOLISM , THERAPY


Subject Categories : Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE