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

Oshima, Nobu; Ishida, Ryoji; Kishimoto, Shun; Beebe, Kristin; Brender, Jeffrey R.; Yamamoto, Kazutoshi; Rai, Ganesha; Johnson, Michelle S.; Benavides, Gloria A.; Squadrito, G; Crooks, Dan; Jackson, Joseph W.; Joshi, Abhinav; Mott, Bryan T.; Shrimp, Jonathan H.; Moses, Michael A.; Lee, Min-Jung; Yuno, Akira; Lee, Tobie; Hu, Xin; Anderson, Tamara L.; Kusewitt, Donna F.; 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.; Maloney, David J.; Dang, Chi V.; Waterson, Alex G.; Hall, Matthew D.; Darley‐Usmar, Victor; Krishna, Murali C.; Neckers, Len

doi:10.2139/ssrn.3456298

Cited by 10 publications

(15 citation statements)

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“…A single dose of a LDHi in this model of hepatocellular carcinoma slowed tumor growth in a dosedependent manner suggesting that higher doses, repeat injections, or local administration may enable tumor regression and/or mitigate hepatocellular carcinoma recurrence. Previous studies have demonstrated that LDH inhibition may reduce tumor doubling times in several cancers and that myc-driven tumors, including hepatoblastoma, have enhanced LDH activity; however, in vivo LDH targeting in hepatocellular carcinoma has not been demonstrated previously (5,43,44). In addition, while the observed LDHi-induced reduction in lactate production was anticipated, the degree of LDH inhibition observed in our study is unique (23,43,45).…”

Section: Discussioncontrasting

confidence: 54%

“…Previous studies have demonstrated that LDH inhibition may reduce tumor doubling times in several cancers and that myc-driven tumors, including hepatoblastoma, have enhanced LDH activity; however, in vivo LDH targeting in hepatocellular carcinoma has not been demonstrated previously (5,43,44). In addition, while the observed LDHi-induced reduction in lactate production was anticipated, the degree of LDH inhibition observed in our study is unique (23,43,45). These data, in combination with the genetic screening data, demonstrate that hepatocellular carcinoma is more susceptible to LDH inhibition than other cancers.…”

Section: Discussionmentioning

confidence: 99%

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Functional Genetic Screening Enables Theranostic Molecular Imaging in Cancer

Perkons

Johnson

Pilla

et al. 2020

Clinical Cancer Research

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◥Purpose: Targeted therapies for cancer have accelerated the need for functional imaging strategies that inform therapeutic efficacy. This study assesses the potential of functional genetic screening to integrate therapeutic target identification with imaging probe selection through a proof-of-principle characterization of a therapyprobe pair using dynamic nuclear polarization (DNP)-enhanced magnetic resonance spectroscopic imaging (MRSI).Experimental Design: CRISPR-negative selection screens from a public dataset were used to identify the relative dependence of 625 cancer cell lines on 18,333 genes. Follow-up screening was performed in hepatocellular carcinoma with a focused CRISPR library targeting imaging-related genes. Hyperpolarized [1-13 C]-pyruvate was injected before and after lactate dehydrogenase inhibitor (LDHi) administration in male Wistar rats with autochthonous hepatocellular carcinoma. MRSI evaluated intratumoral pyruvate metabolism, while T 2 -weighted segmentations quantified tumor growth.Results: Genetic screening data identified differential metabolic vulnerabilities in 17 unique cancer types that could be imaged with existing probes. Among these, hepatocellular carcinoma required lactate dehydrogenase (LDH) for growth more than the 29 other cancer types in this database. LDH inhibition led to a decrease in lactate generation (P < 0.001) and precipitated dose-dependent growth inhibition (P < 0.01 overall, P < 0.05 for dose dependence). Intratumoral alanine production after inhibition predicted the degree of growth reduction (P < 0.001).Conclusions: These findings demonstrate that DNP-MRSI of LDH activity using hyperpolarized [1-13 C]-pyruvate is a theranostic strategy for hepatocellular carcinoma, enabling quantification of intratumoral LDHi pharmacodynamics and therapeutic efficacy prediction. This work lays the foundation for a novel theranostic platform wherein functional genetic screening informs imaging probe selection to quantify therapeutic efficacy on a cancer-bycancer basis.

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Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Functional Genetic Screening Enables Theranostic Molecular Imaging in Cancer

Perkons

Johnson

Pilla

et al. 2020

Clinical Cancer Research

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“…Lactate dehydrogenase (LDH) and hexokinase 2 (HK2) inhibition, two key enzymes within glycolysis, has shown efficacy in pre-clinical models (Fantin et al, 2006;Patra et al, 2013). Recent work demonstrated that LDH inhibition in glycolytic tumors leads to redirection of pyruvate to support mitochondrial metabolism, creating a vulnerability to combination therapy with a mitochondrial ETC inhibitor such as metformin (Oshima et al, 2020). HK2 loss in adult mice is well tolerated and, importantly, its inhibition does not affect T cell function (Mehta et al, 2018).…”

Section: Combining Mitochondrial Metabolism Inhibitors With Other Anti-cancer Agentsmentioning

confidence: 99%

Mitochondrial Metabolism as a Target for Cancer Therapy

2020

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Recent evidence in humans and mice supports the notion that mitochondrial metabolism is active and necessary for tumor growth. Mitochondrial metabolism supports tumor anabolism by providing key metabolites for macromolecule synthesis and generating oncometabolites to maintain the cancer phenotype. Moreover, there are multiple clinical trials testing the efficacy of inhibiting mitochondrial metabolism as a new cancer therapeutic treatment. In this review, we discuss the rationale of using these anti-cancer agents in clinical trials and highlight how to effectively utilize them in different tumor contexts.

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“…Specifically it has been shown that LDH suppression induces oxidative stress and reduces tumor progression [ 190 , 191 ]. Its association to the inhibition of four glycolysis pathway molecules (GLUT1, HKII, PFKFB3, PDHK1) using WZB117, 3PO, 3-bromopyruvate, Dichloroacetate inhibitors (Phloretin, Quercetin, STF31Oxamic acid, NHI-1) results in an increase of extracellular glucose, a decrease of lactate production and a rise in apoptosis of cancer cells [ 192 ]. In MIA PaCa-2 human pancreatic cells, the inhibition of LDHA by GNE-140 for 2 days was found to trigger cell death, although the activation of the AMPK-mTOR-S6K signaling induced resistance to GNE-140 and increased oxidative phosphorylation [ 193 ].…”

Section: The Warburg Effect and Tumor Therapymentioning

confidence: 99%

The Warburg Effect 97 Years after Its Discovery

Pascale

Calvisi

Simile

et al. 2020

Cancers

171

118

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The deregulation of the oxidative metabolism in cancer, as shown by the increased aerobic glycolysis and impaired oxidative phosphorylation (Warburg effect), is coordinated by genetic changes leading to the activation of oncogenes and the loss of oncosuppressor genes. The understanding of the metabolic deregulation of cancer cells is necessary to prevent and cure cancer. In this review, we illustrate and comment the principal metabolic and molecular variations of cancer cells, involved in their anomalous behavior, that include modifications of oxidative metabolism, the activation of oncogenes that promote glycolysis and a decrease of oxygen consumption in cancer cells, the genetic susceptibility to cancer, the molecular correlations involved in the metabolic deregulation in cancer, the defective cancer mitochondria, the relationships between the Warburg effect and tumor therapy, and recent studies that reevaluate the Warburg effect. Taken together, these observations indicate that the Warburg effect is an epiphenomenon of the transformation process essential for the development of malignancy.

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

Cited by 10 publications

References 0 publications

Functional Genetic Screening Enables Theranostic Molecular Imaging in Cancer

Functional Genetic Screening Enables Theranostic Molecular Imaging in Cancer

Mitochondrial Metabolism as a Target for Cancer Therapy

The Warburg Effect 97 Years after Its Discovery

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