Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma

Gwynne, William D.; Suk, Yujin; Custers, Stefan; Mikolajewicz, Nicholas; Chan, Jeremy K; Zádor, Zsolt; Chafe, Shawn C.; Zhai, Kui; Escudero, Laura; Zhang, Cunjie; Zaslaver, Olga; Chokshi, Chirayu; Shaikh, Muhammad Vaseem; Bakhshinyan, David; Burns, Ian; Chaudhry, Iqra; Nachmani, Omri; Mobilio, Daniel; Maich, William; Mero, Patricia; Brown, Kevin R.; Quaile, Andrew T.; Venugopal, Chitra; Moffat, Jason; Montenegro-Burke, J. Rafael; Singh, Sheila K.

doi:10.1016/j.ccell.2022.10.009

Cited by 32 publications

(24 citation statements)

References 72 publications

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“…While de novo synthesis of both purines and pyrimidines is elevated in GBM compared to cortex, salvage of uridine and hypoxanthine appears to dominate nucleotide production. This situation appears to differ from that of other brain tumors, where the de novo synthesis of pyrimidines is critical [48][49][50] . These results suggest that targeting the upstream steps of de novo nucleotide synthesis in GBM may lack efficacy due to compensatory salvage pathways that can fill nucleotide pools when upstream steps are blocked.…”

Section: Discussionmentioning

confidence: 79%

Rewiring of cortical glucose metabolism fuels human brain cancer growth

Scott,

Mittal,

Meghdadi

et al. 2023

Preprint

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The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth.

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Section: Discussionmentioning

confidence: 79%

Rewiring of cortical glucose metabolism fuels human brain cancer growth

Scott,

Mittal,

Meghdadi

et al. 2023

Preprint

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“…Why would cells evolve to preferentially rely on GTP signaling to stimulate DNA repair? Does the primacy for GTP in controlling DNA repair hold true even for cancers that are especially reliant on de novo pyrimidine synthesis for growth (46)(47)(48). Understanding this issue will determine how best to sequence and combine inhibitors of purine and pyrimidine synthesis with standard of care genotoxic agents for these cancers.…”

Section: Discussionmentioning

confidence: 99%

GTP signaling links metabolism, DNA repair, and responses to genotoxic stress

Zhou

Zhao

Lin

et al. 2023

Preprint

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How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.

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“…Human dihydroorotate dehydrogenase (DHODH) catalyzes the dehydrogenation of dihydroorotate (DHO) to orotate (ORO). This process belongs to the fourth step of the de novo synthesis pathway of pyrimidine, therefore hDHODH is a key enzyme in the synthesis of nucleic acid pyrimidine (Gehlot & Vyas, 2023;Cao et al, 2023;Zhang et al, 2022;Madak et al, 2019;Gwynne et al, 2022). Inhibiting hDHODH can block the synthesis of new pyrimidine, resulting in a blockage of DNA and RNA synthesis.…”

Section: Introductionmentioning

confidence: 99%

Discovery a series of novel inhibitors of human dihydroorotate dehydrogenase: Biological activity evaluation and molecular docking

Ren,

Liu,

Hua

et al. 2023

Chem Biol Drug Des

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Human dihydroorotate dehydrogenase (hDHODH) is a key enzyme that catalyzes the de novo synthesis of pyrimidine. In recent years, various studies have shown that inhibiting this enzyme can treat autoimmune diseases such as rheumatoid arthritis (RA) and cancer. This study designed and synthesized a series of novel thiazolidone hDHODH inhibitors. Through biological activity evaluation, Compound 14 was found to have high inhibitory activity, with an IC50 value reaching nanomolar level. Preliminary structure–activity relationship studies found that the carboxyl group in R1 and the naphthalene in R2 are key factors in improving activity. Through molecular docking, the binding mode between inhibitors and proteins was elucidated. This study provides an important reference for further optimizing hDHODH inhibitors.

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Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma

Cited by 32 publications

References 72 publications

Rewiring of cortical glucose metabolism fuels human brain cancer growth

Rewiring of cortical glucose metabolism fuels human brain cancer growth

GTP signaling links metabolism, DNA repair, and responses to genotoxic stress

Discovery a series of novel inhibitors of human dihydroorotate dehydrogenase: Biological activity evaluation and molecular docking

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