Yunyun Chen1, Anastasios Maniakas1,2, Lin Tan3, Meng Cui1,4, Xiangdong Le1, Joshua S Niedzielski5, Keith A Michel5, Collin J Harlan5, Wuhao Lu6,7, Ying C Henderson1, Abdallah S R Mohamed8,9, Philip L Lorenzi3, Nagireddy Putluri10, James A Bankson5, Vlad C Sandulache11, Stephen Y Lai12,13,14. 1. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2. Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, QC, Canada. 3. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 4. Department of Head Neck and Thyroid, Henan Cancer Hospital affiliated to Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China. 5. Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 6. Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA. 7. Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. 8. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 9. MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. 10. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. 11. Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA. Vlad.Sandulache@bcm.edu. 12. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sylai@mdanderson.org. 13. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sylai@mdanderson.org. 14. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sylai@mdanderson.org.
Abstract
BACKGROUND: Lactate dehydrogenase (LDH) is a critical metabolic enzyme. LDH A (LDHA) overexpression is a hallmark of aggressive malignancies and has been linked to tumour initiation, reprogramming and progression in multiple tumour types. However, successful LDHA inhibition strategies have not materialised in the translational and clinical space. We sought to develop a rational strategy for LDHA suppression in the context of solid tumour treatment. METHODS: We utilised a doxycycline-inducible short hairpin RNA (shRNA) system to generate LDHA suppression. Lactate and LDH activity levels were measured biochemically and kinetically using hyperpolarised 13C-pyruvate nuclear magnetic resonance spectroscopy. We evaluated effects of LDHA suppression on cellular proliferation and clonogenic survival, as well as on tumour growth, in orthotopic models of anaplastic thyroid carcinoma (ATC) and head and neck squamous cell carcinoma (HNSCC), alone or in combination with radiation. RESULTS: shRNA suppression of LDHA generated a time-dependent decrease in LDH activity with transient shifts in intracellular lactate levels, a decrease in carbon flux from pyruvate into lactate and compensatory shifts in metabolic flux in glycolysis and the Krebs cycle. LDHA suppression decreased cellular proliferation and temporarily stunted tumour growth in ATC and HNSCC xenografts but did not by itself result in tumour cure, owing to the maintenance of residual viable cells. Only when chronic LDHA suppression was combined with radiation was a functional cure achieved. CONCLUSIONS: Successful targeting of LDHA requires exquisite dose and temporal control without significant concomitant off-target toxicity. Combinatorial strategies with conventional radiation are feasible as long as the suppression is targeted, prolonged and non-toxic.
BACKGROUND: Lactate dehydrogenase (LDH) is a critical metabolic enzyme. LDH A (LDHA) overexpression is a hallmark of aggressive malignancies and has been linked to tumour initiation, reprogramming and progression in multiple tumour types. However, successful LDHA inhibition strategies have not materialised in the translational and clinical space. We sought to develop a rational strategy for LDHA suppression in the context of solid tumour treatment. METHODS: We utilised a doxycycline-inducible short hairpin RNA (shRNA) system to generate LDHA suppression. Lactate and LDH activity levels were measured biochemically and kinetically using hyperpolarised 13C-pyruvate nuclear magnetic resonance spectroscopy. We evaluated effects of LDHA suppression on cellular proliferation and clonogenic survival, as well as on tumour growth, in orthotopic models of anaplastic thyroid carcinoma (ATC) and head and neck squamous cell carcinoma (HNSCC), alone or in combination with radiation. RESULTS: shRNA suppression of LDHA generated a time-dependent decrease in LDH activity with transient shifts in intracellular lactate levels, a decrease in carbon flux from pyruvate into lactate and compensatory shifts in metabolic flux in glycolysis and the Krebs cycle. LDHA suppression decreased cellular proliferation and temporarily stunted tumour growth in ATC and HNSCC xenografts but did not by itself result in tumour cure, owing to the maintenance of residual viable cells. Only when chronic LDHA suppression was combined with radiation was a functional cure achieved. CONCLUSIONS: Successful targeting of LDHA requires exquisite dose and temporal control without significant concomitant off-target toxicity. Combinatorial strategies with conventional radiation are feasible as long as the suppression is targeted, prolonged and non-toxic.
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