The biological role of metabolic reprogramming in pancreatic cancer

Suzuki, Tatsunori; Otsuka, Motoyuki; Seimiya, Takahiro; Iwata, Takuma; Kishikawa, Takahiro; Koike, Kazuhiko

doi:10.1002/mco2.37

Cited by 16 publications

(6 citation statements)

References 95 publications

(127 reference statements)

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“…Mutant KRAS activates a diverse spectrum of downstream effector proteins [ 17 ], particularly components of the mitogen-activated protein kinase (MAPK) pathway and of the phosphoinositide-3-kinase (PI3K) pathway. KRAS mutation in PDAC is critical for reprogramming intracellular metabolism of, for example, glucose and glutamine, to facilitate the rapid proliferation of cancer cells [ 18 – 27 ]. To acquire sufficient nutrients for rapid proliferation, PDAC has elevated basal autophagy [ 28 – 30 ] in which biomolecules digested in lysosomes become available as nutrients [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells

et al. 2021

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Mutational activation of the KRAS gene occurs in almost all pancreatic ductal adenocarcinoma (PDAC) and is the earliest molecular event in their carcinogenesis. Evidence has accumulated of the metabolic reprogramming in PDAC, such as amino acid homeostasis and autophagic flux. However, the biological effects of KRAS mutation on metabolic reprogramming at the earlier stages of PDAC carcinogenesis are unclear. Here we report dynamic metabolic reprogramming in immortalized human non-cancerous pancreatic ductal epithelial cells, in which a KRAS mutation was induced by gene-editing, which may mimic early pancreatic carcinogenesis. Similar to the cases of PDAC, KRAS gene mutation increased the dependency on glucose and glutamine for maintaining the intracellular redox balance. In addition, the intracellular levels of amino acids were significantly decreased because of active protein synthesis, and the cells required greater autophagic flux to maintain their viability. The lysosomal inhibitor chloroquine significantly inhibited cell proliferation. Therefore, metabolic reprogramming is an early event in carcinogenesis initiated by KRAS gene mutation, suggesting a rationale for the development of nutritional interventions that suppress or delay the development of PDAC.

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Section: Introductionmentioning

confidence: 99%

Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells

et al. 2021

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“… 25 This distinctive extracellular milieu results in relative energy restriction and lends itself to be exploited as a possible metabolic vulnerability. 26 27 As PDAC is characterised by metabolic reprogramming, 28 29 interventions aimed to target key metabolic processes are being actively investigated as potential anti-cancer therapies for PDAC (NCT02514031, NCT00096707, NCT03504423, NCT00741403, NCT03699319).…”

Section: Discussionmentioning

confidence: 99%

Repurposing the FDA-approved anthelmintic pyrvinium pamoate for pancreatic cancer treatment: study protocol for a phase I clinical trial in early-stage pancreatic ductal adenocarcinoma

Ponzini,

Schultz,

Leiby

et al. 2023

BMJ Open

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BackgroundRecent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical models. Here, we report about an ongoing phase I open-label, single-arm, dose escalation clinical trial to determine the safety and tolerability of PP in PDAC surgical candidates.Methods and analysisIn a 3+3 dose design, PP is initiated 3 days prior to surgery. The first three patients will be treated with the initial dose of PP at 5 mg/kg orally for 3 days prior to surgery. Dose doubling will be continued to a reach a maximum of 20 mg/kg orally for 3 days, if the previous two dosages (5 mg/kg and 10 mg/kg) were tolerated. Dose-limiting toxicity grade≥3 is used as the primary endpoint. The pharmacokinetic and pharmacodynamic (PK/PD) profile of PP and bioavailability in humans will be used as the secondary objective. Each participant will be monitored weekly for a total of 30 days from the final dose of PP for any side effects. The purpose of this clinical trial is to examine whether PP is safe and tolerable in patients with pancreatic cancer, as well as assess the drug’s PK/PD profile in plasma and fatty tissue. Potential implications include the utilisation of PP in a synergistic manner with chemotherapeutics for the treatment of pancreatic cancer.Ethics and disseminationThis study was approved by the Thomas Jefferson Institutional Review Board. The protocol number for this study is 20F.041 (Version 3.1 as of 27 October 2021). The data collected and analysed from this study will be used to present at local and national conferences, as well as, written into peer-reviewed manuscript publications.Trial registration numberClinicalTrials.gov:NCT05055323.

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“…[26][27][28] This mutation is the initial event in PDAC, boosting its resistance to glucose and glutamine dependency, thereby promoting intracellular redox balance. [29][30][31][32] This metabolic shift, evident from an increase in glucose transporter 1 (GLUT1), indicates that KRAS mutations instigate metabolic reprogramming in early PDAC stages. [33,34] Kras G12D alters the metabolism of PDAC by means of the mitogen-activated protein kinase (MAPK) and myelocytomatosis oncogene (MYC) pathways.…”

Section: Key Gene Mutation and Metabolismmentioning

confidence: 99%

Metabolic signatures in pancreatic ductal adenocarcinoma: diagnostic and therapeutic implications

Gong,

Hu,

et al. 2023

Journal of Pancreatology

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Pancreatic ductal adenocarcinoma (PDAC) is the prototypical aggressive cancer that develops in nutrient-deficient and hypoxic microenvironment. PDAC overcomes these restrictions by employing unconventional tactics for the procurement and usage of fuel sources. The substantial reprogramming of PDAC cells metabolism is driven by oncogene-mediated cell-autonomous pathways. PDAC cells use glucose, glutamine, and lipids for energy and depend on autophagy and macropinocytosis for survival and growth. They also interact metabolically with non-cancerous cells, aiding tumor progression. Many clinical trials focusing on altered metabolism are ongoing. Understanding the metabolic regulation of PDAC cells will not only help to increase understanding of the mechanisms of disease progression, but also provide insights for the development of new diagnostic and therapeutic approaches.

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The biological role of metabolic reprogramming in pancreatic cancer

Cited by 16 publications

References 95 publications

Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells

Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells

Repurposing the FDA-approved anthelmintic pyrvinium pamoate for pancreatic cancer treatment: study protocol for a phase I clinical trial in early-stage pancreatic ductal adenocarcinoma

Metabolic signatures in pancreatic ductal adenocarcinoma: diagnostic and therapeutic implications

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