Clinical development of metabolic inhibitors for oncology

Lemberg, Kathryn M.; Gori, Sadakatali S.; Tsukamoto, Takashi; Rais, Rana; Slusher, Barbara S.

doi:10.1172/jci148550

Cited by 73 publications

(50 citation statements)

References 143 publications

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“…Only a few metabolism-based drugs for cancer have been successfully developed, and some of them are currently being tested in clinical trials. Detailed descriptions about the currently available pharmacological compounds acting on metabolism together with the up-to-date clinical trials on tumors have been recently reviewed elsewhere ( Lemberg et al, 2022 ; Stine et al, 2022 ). In this work, we have performed an unprecedented review of metabolism-related features of MB, detailing MB subgroup-specific metabolic alterations ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Marabitti

Giansanti²,

Mitri³

et al. 2022

Front. Cell Dev. Biol.

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Tumor-specific alterations in metabolism have been recognized to sustain the production of ATP and macromolecules needed for cell growth, division and survival in many cancer types. However, metabolic heterogeneity poses a challenge for the establishment of effective anticancer therapies that exploit metabolic vulnerabilities. Medulloblastoma (MB) is one of the most heterogeneous malignant pediatric brain tumors, divided into four molecular subgroups (Wingless, Sonic Hedgehog, Group 3 and Group 4). Recent progresses in genomics, single-cell sequencing, and novel tumor models have updated the classification and stratification of MB, highlighting the complex intratumoral cellular diversity of this cancer. In this review, we emphasize the mechanisms through which MB cells rewire their metabolism and energy production networks to support and empower rapid growth, survival under stressful conditions, invasion, metastasis, and resistance to therapy. Additionally, we discuss the potential clinical benefits of currently available drugs that could target energy metabolism to suppress MB progression and increase the efficacy of the current MB therapies.

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Section: Discussionmentioning

confidence: 99%

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Marabitti

Giansanti²,

Mitri³

et al. 2022

Front. Cell Dev. Biol.

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“…In clinic, the most advanced FAS inhibitor reported to date is TVB-2640. Combined to taxane in advanced cancers, it shows promising safety profile in first-in-human study, therefore, a phase II trial is ongoing [ 134 ]. Finally, in sorafenib-resistant HCC tumors, disruption of over-activated monounsaturated FA synthesis with SCD1 inhibitor (i.e., SSI-4) enhances sorafenib-induced tumor regression via an activation of ER-stress response [ 135 ].…”

Section: Introductionmentioning

confidence: 99%

Lipids in cancer: a global view of the contribution of lipid pathways to metastatic formation and treatment resistance

Vasseur

Guillaumond

2022

Oncogenesis

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Lipids are essential constituents for malignant tumors, as they are absolutely required for tumor growth and dissemination. Provided by the tumor microenvironment (TME) or by cancer cells themselves through activation of de novo synthesis pathways, they orchestrate a large variety of pro-tumorigenic functions. Importantly, TME cells, especially immune cells, cancer-associated fibroblasts (CAFs) and cancer-associated adipocytes (CAAs), are also prone to changes in their lipid content, which hinder or promote tumor aggressiveness. In this review, we address the significant findings for lipid contribution in tumor progression towards a metastatic disease and in the poor response to therapeutic treatments. We also highlight the benefits of targeting lipid pathways in preclinical models to slow down metastasis development and overcome chemo-and immunotherapy resistance.

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“…Increasing evidence has revealed that metabolic reprogramming impacts oncogenesis and the TME ( 32 , 33 ). Metabolic gene changes and their clinical impacts have been reported in multiple cancer types, indicating that altered metabolism-related genes may serve as promising therapeutic targets in cancer ( 16 , 34 ).…”

Section: Discussionmentioning

confidence: 99%

Statin shapes inflamed tumor microenvironment and enhances immune checkpoint blockade in non–small cell lung cancer

Mao¹,

Cai²,

Chen³

et al. 2022

JCI Insight

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Immune checkpoint blockade (ICB) therapy has achieved breakthroughs in the treatment of advanced non-small cell lung cancer (NSCLC). Nevertheless, the low response due to immuno-cold tumor microenvironment (TME) largely limits the application of ICB therapy. Based on the glycolytic/cholesterol synthesis axis, a stratification framework for EGFR wild-type NSCLC was developed to summarize the metabolic features of immuno-cold and immuno-hot tumors. The cholesterol subgroup displays the worst prognosis in immuno-cold NSCLC with significant enrichment of the cholesterol gene signature, indicating targeting cholesterol synthesis is essential for the therapy for immuno-cold NSCLC. Statin, the inhibitor for cholesterol synthesis, can suppress the aggressiveness of NSCLC in vitro and in vivo and also drastically reverse immuno-cold to an inflamed phenotype in vivo which exhibited a higher response to ICB therapy. Moreover, both our in-house data and meta-analysis further support that statin can significantly enhance ICB efficacy. In terms of preliminary mechanisms, statin could transcriptionally inhibit PD-L1 expression and induce ferroptosis in NSCLC cells. Overall, we reveal the significance of cholesterol synthesis in NSCLC and demonstrate the improved therapeutic efficacy of ICB in combination with statin.These findings could provide a innovative clinical insight to treat NSCLC patients with immuno-cold tumors.

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Clinical development of metabolic inhibitors for oncology

Cited by 73 publications

References 143 publications

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Lipids in cancer: a global view of the contribution of lipid pathways to metastatic formation and treatment resistance

Statin shapes inflamed tumor microenvironment and enhances immune checkpoint blockade in non–small cell lung cancer

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