Targeting pyrimidine synthesis accentuates molecular therapy response in glioblastoma stem cells

Wang, Xiuxing; Yang, Kailin; Wu, Qiulian; Kim, Leo J.Y.; Morton, Andrew; Gimple, Ryan C.; Prager, Briana C.; Shi, Yu; Zhou, Wenchao; Bhargava, Shruti; Zhu, Zhe; Jiang, Li; Tao, Weiwei; Qiu, Zhixin; Zhao, Linjie; Zhang, Guoxing; Li, Xiqing; Agnihotri, Sameer; Mischel, Paul S.; Mack, Stephen C.; Bao, Shideng; Rich, Jeremy

doi:10.1126/scitranslmed.aau4972

Cited by 131 publications

(112 citation statements)

References 72 publications

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“…In this regard, a recent study demonstrated the benefit of blocking pyrimidine synthesis using teriflunomide in conjunction with PI3K inhibitor BKM120 to increase the inhibition of glioblastoma tumorigenesis in a xenograft model. (49) For our study, we observed a synergistic effect of combining MPA with PI-103 or HLM006474 in attenuating the proliferation of Huh7 cells and a PDX organoid culture (PDX #11). PDX #11 exhibited highest inherent purine synthetic activity among all PDX lines and therefore had the most severely impacted viability by MPA treatment.…”

Section: Discussionmentioning

confidence: 59%

Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression

et al. 2020

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We demonstrate that in human HCCs with deregulated expression of purine metabolic enzymes, targeting purine metabolism was effective in blocking tumor cell proliferation, leading to tumor shrinkage. Precise regulation of purine metabolic activity was coordinated by the activation status of a PI3K‐E2F1 axis, and potent suppression of purine metabolism via combinatorial targeting of PI3K and the purine synthetic rate‐limiting enzyme IMPDH resulted in enhanced efficacy in a pre‐clinical model. These data provide a strong basis for future precision‐medicine focused clinical trials targeting this tumor‐specific metabolic adaptation as a point of vulnerability in patients with HCC.

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Section: Discussionmentioning

confidence: 59%

Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression

et al. 2020

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“…The de novo pyrimidine synthesis pathway is a promising target for biomedical and biotechnological intervention [51][52][53][54][55] . Our analysis has uncovered the unique regulatory and catalytic mechanisms of plant ATCs, suggesting new strategies to modulate this central enzymatic activity and thus, inhibit or enhance plant growth in a similar manner as we have shown by down-or upregulating ATC expression ( Fig.…”

Section: Discussionmentioning

confidence: 99%

UMP inhibition and sequential firing in aspartate transcarbamoylase open ways to regulate plant growth

Bellin

Caño-Ochoa

Velázquez‐Campoy

et al. 2020

Preprint

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Pyrimidine nucleotides are essential to plant development. We proved that Arabidopsis growth can be inhibited or enhanced by down- or upregulating aspartate transcarbamoylase (ATC), the first committed enzyme for de novo biosynthesis of pyrimidines in plants. To understand the unique mechanism of feedback inhibition of this enzyme by uridine 5-monophosphate (UMP), we determined the crystal structure of the Arabidopsis ATC trimer free and bound to UMP, demonstrating that the nucleotide binds and blocks the active site. The regulatory mechanism relies on a loop exclusively conserved in plants, and a single-point mutation (F161A) turns ATC insensitive to UMP. Moreover, the structures in complex with a transition-state analog or with carbamoyl phosphate proved a mechanism in plant ATCs for sequential firing of the active sites. The disclosure of the unique regulatory and catalytic properties suggests new strategies to modulate ATC activity and to control de novo pyrimidine synthesis and plant growth.

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“…The maintenance of high-rate pyrimidine synthesis may be limiting for gliomas, and targeting this pathway resulted in decreased viability of GBM stem cells [30]. Additionally, decreased nutrient availability leads to activation of the catabolic process to provide substrates for biosynthesis.…”

Section: Glutamine Addiction In Gliomasmentioning

confidence: 99%

Targeting Glutamine Addiction in Gliomas

Obara-Michlewska

Szeliga

2020

Cancers

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The most common malignant brain tumors are those of astrocytic origin, gliomas, with the most aggressive glioblastoma (WHO grade IV) among them. Despite efforts, medicine has not made progress in terms of the prognosis and life expectancy of glioma patients. Behind the malignant phenotype of gliomas lies multiple genetic mutations leading to reprogramming of their metabolism, which gives those highly proliferating cells an advantage over healthy ones. The so-called glutamine addiction is a metabolic adaptation that supplements oxidative glycolysis in order to secure neoplastic cells with nutrients and energy in unfavorable conditions of hypoxia. The present review aims at presenting the research and clinical attempts targeting the different metabolic pathways involved in glutamine metabolism in gliomas. A brief description of the biochemistry of glutamine transport, synthesis, and glutaminolysis, etc. will forego a detailed comparison of the therapeutic strategies undertaken to inhibit glutamine utilization by gliomas.

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Targeting pyrimidine synthesis accentuates molecular therapy response in glioblastoma stem cells

Cited by 131 publications

References 72 publications

Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression

Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression

UMP inhibition and sequential firing in aspartate transcarbamoylase open ways to regulate plant growth

Targeting Glutamine Addiction in Gliomas

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