Inhibition of Pyruvate Dehydrogenase Kinase Enhances the Antitumor Efficacy of Oncolytic Reovirus

Kennedy, Barry E.; Murphy, John P.; Clements, Derek R.; Konda, Prathyusha; Holay, Namit; Kim, Youra; Pathak, Gopal P.; Giacomantonio, Michael; Hiani, Yassine El; Gujar, Shashi

doi:10.1158/0008-5472.can-18-2414

Cited by 23 publications

(28 citation statements)

References 41 publications

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“…Therefore, metabolic reprogramming is a promising approach to increase the therapeutic potential of reovirus in cancer patients [163]. Another interesting study found that pre-conditioning tumours with bevacizumab-a vascular endothelial growth factor (VEGF) inhibitor-and then withdrawing treatment, rendered endothelial cells susceptible to reovirus infection, induced vascular collapse and promoted immune-mediated tumour clearance [164].…”

Section: Unlocking the Potential Of Reovirus With Combination Therapeuticsmentioning

confidence: 99%

Past, Present and Future of Oncolytic Reovirus

Müller

Berkeley

Barr

et al. 2020

Cancers

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Oncolytic virotherapy (OVT) has received significant attention in recent years, especially since the approval of talimogene Laherparepvec (T-VEC) in 2015 by the Food and Drug administration (FDA). Mechanistic studies of oncolytic viruses (OVs) have revealed that most, if not all, OVs induce direct oncolysis and stimulate innate and adaptive anti-tumour immunity. With the advancement of tumour modelling, allowing characterisation of the effects of tumour microenvironment (TME) components and identification of the cellular mechanisms required for cell death (both direct oncolysis and anti-tumour immune responses), it is clear that a “one size fits all” approach is not applicable to all OVs, or indeed the same OV across different tumour types and disease locations. This article will provide an unbiased review of oncolytic reovirus (clinically formulated as pelareorep), including the molecular and cellular requirements for reovirus oncolysis and anti-tumour immunity, reports of pre-clinical efficacy and its overall clinical trajectory. Moreover, as it is now abundantly clear that the true potential of all OVs, including reovirus, will only be reached upon the development of synergistic combination strategies, reovirus combination therapeutics will be discussed, including the limitations and challenges that remain to harness the full potential of this promising therapeutic agent.

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Section: Unlocking the Potential Of Reovirus With Combination Therapeuticsmentioning

confidence: 99%

Past, Present and Future of Oncolytic Reovirus

Müller

Berkeley

Barr

et al. 2020

Cancers

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“…A recent study showed that using 2-deoxyglucose (2DG) to block glycolysis or through restricting glucose amount will enhance oncolytic adenoviruses activity in permissive and poorly permissive cancer cells [28]. Furthermore, pyruvate dehydrogenase kinase inhibition showed to improve reovirus oncolytic anti-tumor efficacy in several cancer types [29]. We reported previously that 2DG would enhance oncolytic NDV against breast cancer cells through glycolysis inhibition by downregulation of glyceraldehyde3-phosphate (GAPDH) [30].…”

Section: Introductionmentioning

confidence: 99%

Hexokinase inhibition using D-Mannoheptulose enhances oncolytic newcastle disease virus-mediated killing of breast cancer cells

et al. 2020

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Background: Most cancer cells exhibit increased glycolysis and use this metabolic pathway cell growth and proliferation. Targeting cancer cells' metabolism is a promising strategy in inhibiting cancer cell progression. We used D-Mannoheptulose, a specific hexokinase inhibitor, to inhibit glycolysis to enhance the Newcastle disease virus antitumor effect. Methods: Human breast cancer cells were treated by NDV and/or hexokinase inhibitor. The study included cell viability, apoptosis, and study levels of hexokinase enzyme, pyruvate, ATP, and acidity. The combination index was measured to determine the synergism of NDV and hexokinase inhibitor. Results: The results showed synergistic cytotoxicity against breast cancer cells by combination therapy but no cytotoxic effect against normal cells. The effect was accompanied by apoptotic cell death and hexokinase downregulation and inhibition to glycolysis products, pyruvate, ATP, and acidity. Conclusions: The combination treatment showed safe significant tumor cell proliferation inhibition compared to monotherapies suggesting a novel strategy for anti-breast cancer therapy through glycolysis inhibition by hexokinase downregulation.

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“…Furthermore, an increase in ceramide level has been implicated in the activation of the CD95 death receptor, induction of autophagy, and enhancement of cytotoxicity [23,24]. Knock down of ceramide synthase 6 suppressed autophagosome formation and cell death in breast cancer cells.…”

Section: Metabolites Associated With the Adenovirus-induced Autophagimentioning

confidence: 99%

Metabolome-Driven Regulation of Adenovirus-Induced Cell Death

Laevskaya

Borovjagin

Timashev

et al. 2021

IJMS

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A viral infection that involves virus invasion, protein synthesis, and virion assembly is typically accompanied by sharp fluctuations in the intracellular levels of metabolites. Under certain conditions, dramatic metabolic shifts can result in various types of cell death. Here, we review different types of adenovirus-induced cell death associated with changes in metabolic profiles of the infected cells. As evidenced by experimental data, in most cases changes in the metabolome precede cell death rather than represent its consequence. In our previous study, the induction of autophagic cell death was observed following adenovirus-mediated lactate production, acetyl-CoA accumulation, and ATP release, while apoptosis was demonstrated to be modulated by alterations in acetate and asparagine metabolism. On the other hand, adenovirus-induced ROS production and ATP depletion were demonstrated to play a significant role in the process of necrotic cell death. Interestingly, the accumulation of ceramide compounds was found to contribute to the induction of all the three types of cell death mentioned above. Eventually, the characterization of metabolite analysis could help in uncovering the molecular mechanism of adenovirus-mediated cell death induction and contribute to the development of efficacious oncolytic adenoviral vectors.

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Inhibition of Pyruvate Dehydrogenase Kinase Enhances the Antitumor Efficacy of Oncolytic Reovirus

Cited by 23 publications

References 41 publications

Past, Present and Future of Oncolytic Reovirus

Past, Present and Future of Oncolytic Reovirus

Hexokinase inhibition using D-Mannoheptulose enhances oncolytic newcastle disease virus-mediated killing of breast cancer cells

Metabolome-Driven Regulation of Adenovirus-Induced Cell Death

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