Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy.

Abstract

The reliance of many cancers on aerobic glycolysis has stimulated efforts to develop lactate dehydrogenase (LDH) inhibitors. However, despite significant efforts, LDH inhibitors (LDHi) with sufficient specificity and in vivo activity to determine whether LDH is a feasible drug target are lacking. We describe an LDHi with potent, on-target, in vivo activity. Using hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI), we demonstrate in vivo LDH inhibition in two glycolytic cancer models, MIA PaCa-2 and HT29, and we correlate depth and duration of LDH inhibition with direct anti-tumor activity. HP-MRSI also reveals a metabolic rewiring that occurs in vivo within 30 min of LDH inhibition, wherein pyruvate in a tumor is redirected toward mitochondrial metabolism. Using HP-MRSI, we show that inhibition of mitochondrial complex 1 rapidly redirects tumor pyruvate toward lactate. Inhibition of both mitochondrial complex 1 and LDH suppresses metabolic plasticity, causing metabolic quiescence in vitro and tumor growth inhibition in vivo.

Authors

Oshima, Nobu; Ishida, Ryo; Kishimoto, Shun; Beebe, Kristin; Brender, Jeffrey R; Yamamoto, Kazutoshi; Urban, Daniel; Rai Bantukallu, Ganesha; Johnson, Michelle S; Benavides, Gloria; Squadrito, Giuseppe L; Crooks, Dan; Jackson, Joseph; Joshi, Abhinav; Mott, Bryan T; Shrimp, Jonathan; Moses, Michael A; Lee, Min-Jung; Yuno, Akira; Lee, Tobie D; Hu, Xin; Anderson, Tamara; Kusewitt, Donna; Hathaway, Helen H; Jadhav, Ajit; Picard, Didier; Trepel, Jane B; Mitchell, James B; Stott, Gordon M; Moore, William; Simeonov, Anton; Sklar, Larry A; Norenberg, Jeffrey P; Linehan, W Marston; Maloney, David J; Dang, Chi V; Waterson, Alex G; Hall, Matthew; Darley-Usmar, Victor M; Krishna, Murali C; Neckers, Leonard M;

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