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Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination
Nobu Oshima1, Ryo Ishida1, Shun Kishimoto2
1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
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.
Insights
Researchers developed a novel lactate dehydrogenase inhibitor (LDHi) demonstrating potent in vivo activity against cancer. This LDHi targets aerobic glycolysis, a key cancer mechanism, and shows promise for future cancer therapies.
Area of Science:
- Biochemistry
- Oncology
- Medical Imaging
Background:
- Many cancers rely on aerobic glycolysis for energy.
- Developing specific lactate dehydrogenase inhibitors (LDHis) for cancer treatment has been challenging due to lack of specificity and in vivo efficacy.
Purpose of the Study:
- To develop and evaluate a novel lactate dehydrogenase inhibitor (LDHi) with potent, on-target, in vivo activity.
- To investigate the metabolic effects of LDHi in glycolytic cancer models using hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI).
Main Methods:
- Developed a novel lactate dehydrogenase inhibitor (LDHi).
- Utilized hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI) to assess in vivo LDH inhibition in MIA PaCa-2 and HT29 cancer models.
- Investigated metabolic rewiring and tumor response to LDHi and mitochondrial complex 1 inhibition.
Main Results:
- Demonstrated potent, on-target, in vivo LDH inhibition in two glycolytic cancer models.
- Correlated the depth and duration of LDH inhibition with direct anti-tumor activity.
- Observed rapid metabolic rewiring within 30 minutes of LDHi administration, redirecting pyruvate toward mitochondrial metabolism.
- Showed that inhibiting both mitochondrial complex 1 and LDH suppresses metabolic plasticity, leading to metabolic quiescence and tumor growth inhibition.
Conclusions:
- The novel LDHi exhibits potent in vivo activity, validating LDH as a potential drug target.
- HP-MRSI is effective for monitoring in vivo LDH inhibition and metabolic changes in tumors.
- Targeting both LDH and mitochondrial metabolism offers a strategy to overcome cancer's metabolic plasticity and inhibit tumor growth.
