The biguanide metformin that inhibits mitochondrial complex I activity is now in over 200 oncology clinical trials. In this proposal we will determine how to enhance cancer cell sensitivity towards metformin therapy. There are two principal modes of cellular energy production ? glycolysis and mitochondrial oxidation of glycose and fatty acids. Metformin inhibits mitochondrial energy production. Therefore, when switched to a low glucose medium (that reduces glycolysis), cancer cells become sensitized to metformin. Physiological glucose concentration in tissues is however significantly lower compared to that used in most cell culture studies and glucose concentration is even lower in tumor tissues. At this physiological range of glucose, cancer cells maintain high glycolytic rate and genes that regulate cancer cell glycolysis may resist biguanide action by upregulating compensatory glycolysis when mitochondria is inhibited. Therefore, identification and inhibition of such genes may enhance cancer cell liability towards biguanides. Despite promise in other cancers, our data shows that glioma stem cells (GSCs) are resistant to biguanides at physiological glucose. We discovered that the cellular energy sensor AMP kinase (AMPK) that augments glycolysis during stress in cardiac and skeletal muscle is co-opted by GSCs for optimal glycolysis. We propose to test the mechanisms by which AMPK regulates glycolysis in GSCs in vitro and in vivo. Through dose escalation pharmacological studies in mice we will determine maximum tolerated metformin dose in brain tumor-bearing mice, quantitate metformin plasma levels, and metformin concentrations attained in normal brain and tumor tissue. We will test if genetic inhibition of AMPK in GSCs reduces glycolysis, suppress proliferation and tumor growth and improves metformin sensitivity.

Public Health Relevance

There is a renewed interest to examine mitochondrial function in human cancer following recent discoveries that tumor cell mitochondria regulate various aspects of tumorigenesis. Glioblastoma multiforme (GBM) is an incurable brain tumor with a median survival of 15 months and new therapy is badly needed. The biguanide drug metformin that blocks mitochondrial function is in several oncology clinical trials. We will test the genes that confer resistance to metformin in glioma stem cells. Our studies will hopefully illuminate new avenues in GBM therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS099162-02
Application #
9417097
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Fountain, Jane W
Project Start
2016-02-01
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229