University of Kentucky Center for Cancer and Metabolism (Pilot Project - Dr. Matthew Gentry)

Grants and Contracts Details

Description

Lung cancer is the leading cause of cancer death in the united states. Kentucky leads the nation both in lung cancer incidence and mortality. Glycogen molecule has been identified in several pre-clinical cancer models, however the roles of glycogen metabolism in cancer development and progression are poorly understood nor are glycogen metabolic enzymes explored as therapeutic targets. EPM2A and NHLRC1 are glycogen metabolic enzymes frequently mutated in lafora disease, loss of function for either EPM2A or NHLRC1 has profound impact on glycogen metabolism. In a collaborative effort, we found a significant reduction in EPM2A and NHLRC1 mRNA and protein levels in NSCLC compared to surrounding normal tissues. Additionally, we observed high EPM2A expression strongly correlates with better prognosis and overall survival in NSCLC patients. Furthermore, stem cells isolated from Epm2a-/- mouse lungs form larger 3D-organoids at a faster rate suggesting a role for Epm2a in lung stem cell differentiation. Based on this premise, we hypothesize that NSCLC suppresses EMP2A and NHLRC1 to alter glycogen metabolism and this process drives metabolic reprogramming to facilitate tumorigenesis. We will test out hypotheses via two specific aims: (1) Determine the roles of EPM2A and NHLRC1 in regulating the metabolic landscape of pre-clinical models of NSCLC using SIRM analysis. (2) Define the impact of EPM2A deletion on lung stem cell differentiation and metabolism in 3D-organoids using integrated SIRM and transcriptomics analysis. We hope to advance our understanding of metabolism and regulation of the NSCLC metastatic process and reveal novel drug targets and markers for NSCLC metastasis. Completion of the proposed studies will significantly advance our understanding of the role glycogen metabolism and its regulation play in NSCLC development. This work will also provide a rational basis for future development of novel therapeutic strategies to treat NSCLC. We are confident that data collected from this project will be used for the submission of a competitive R01 grant focusing on identifying and developing small molecule therapeutics against NSCLC.
StatusFinished
Effective start/end date1/1/1812/31/18

Funding

  • National Institute of General Medical Sciences

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