Presentation Authors: Mamatha Garige, Silver Spring, MD, Sandeep Gurram*, Daniel Crooks, Nobu Oshima, Anton Simeonov, Matthew Hall, Gustavo Pena-La Grave, Bethesda, MD, Andrew Lane, Teresa Fan, Lexington, KY, Carole Sourbier, Silver Spring, MD, Murali Cherukuri, Len Neckers, Piyush Agarwal, Bethesda, MD
Introduction: Despite the advent of genomic sequencing, the clinical management of bladder cancer has not changed drastically, and little progress has been made towards more precisely targeted bladder cancer therapies. Perturbed metabolic pathways in tumors constitute a potential opportunity for new therapeutic strategies. Many cancer cell lines exhibit the &[Prime]Warburg Effect,&[Prime] in that they depend on glycolysis more than normal cells. In this study, we targeted the perturbed metabolism in bladder cancer using an inhibitor of lactate dehydrogenase (LDH) developed by our institution's drug development program, with and without the inclusion of metformin.
Methods: Using the Seahorse extra-cellular flux analyzer (Agilent Technologies, Santa Clara, CA), we characterized cell lines based on their extracellular acidification rates (ECAR) and oxygen consumption rates (OCR), to determine their relative reliance on glycolysis or oxidative phosphorylation. The LDH inhibitor was tested in select cell lines for effects on proliferation, invasion, and migration. This inhibitor was also tested in vivo, either as a single agent or in combination with metformin.
Results: For the first time, we bioenergetically profiled fourteen bladder cancer cell lines based on their ECAR and OCR preference. Most bladder cancer cell lines depend on oxidative phosphorylation to various degrees (based on high OCR) but a few rely more heavily on glycolysis (based on high ECAR). The cell lines that relied more heavily on glycolysis were more sensitive to LDH inhibition; however, the other cell lines responded to LDH inhibition when made more glycolytic by either hypoxia or cotreatment with metformin. The UMUC3 xenograft demonstrated decreased growth with LDH inhibition.
Conclusions: These data describe for the first time the metabolic phenotype of bladder cancer cell lines and demonstrate that glycolytic tumors are sensitive to LDH inhibitor. In tumors dependent on oxidative phosphorylation, a combination of LDH inhibitor with metformin may overcome LDH inhibitor resistance.
Source of Funding: This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.