Small‐Molecule Inhibition of Glucose Transporters GLUT‐1–4

Reckzeh, Elena S.; Waldmann, Herbert

doi:10.1002/cbic.201900544

Cited by 67 publications

(49 citation statements)

References 90 publications

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“…The inhibition of the Warburg effect and/or glycolysis—including MCTs—has been the focus of numerous cancer-related studies for the last decade. However, except for in some trials, the success lagged behind expectations due to the toxic side-effects or inefficacy (attributed to metabolic adaptation mechanisms) of the tested agents [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy

Petővári

Dankó

Tőkés

et al. 2020

Cancers

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In spite of tremendous developments in breast cancer treatment, the relatively high incidence of relapsing cases indicates a great need to find new therapeutic strategies in recurrent, metastatic and advanced cases. The bioenergetic needs of growing tumours at the primary site or in metastases—accumulating genomic alterations and further heterogeneity—are supported by metabolic rewiring, an important hallmark of cancer. Adaptation mechanisms as well as altered anabolic and catabolic processes balance according to available nutrients, energy, oxygen demand and overgrowth or therapeutic resistance. Mammalian target of rapamycin (mTOR) hyperactivity may contribute to this metabolic plasticity and progression in breast carcinomas. We set out to assess the metabolic complexity in breast cancer cell lines and primary breast cancer cases. Cellular metabolism and mTOR-related protein expression were characterised in ten cell lines, along with their sensitivity to specific mTOR and other metabolic inhibitors. Selected immunohistochemical reactions were performed on ~100 surgically removed breast cancer specimens. The obtained protein expression scores were correlated with survival and other clinicopathological data. Metabolic and mTOR inhibitor mono-treatments had moderate antiproliferative effects in the studied cell lines in a subtype-independent manner, revealing their high adaptive capacity and survival/growth potential. Immunohistochemical analysis of p-S6, Rictor, lactate dehydrogenase A, glutaminase, fatty acid synthase and carnitine palmitoyltransferase 1A in human samples identified high mTOR activity and potential metabolic plasticity as negative prognostic factors for breast cancer patients, even in subtypes generally considered as low-risk. According to our results, breast cancer is characterised by considerable metabolic diversity, which can be targeted by combining antimetabolic treatments and recent therapies. Alterations in these pathways may provide novel targets for future drug development in breast cancer. We also propose a set of immunostainings for scoring metabolic heterogeneity in individual cases in order to select patients who may benefit from more accurate follow-up and specific therapies.

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Section: Discussionmentioning

confidence: 99%

In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy

Petővári

Dankó

Tőkés

et al. 2020

Cancers

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“…Inhibiting tumor glucose uptake, glycolysis and lactate transport have been proposed to reduce both tumor growth and immunosuppression, thus rendering these strategies compelling candidates for combination therapy. Specific and potent inhibitors of the GLUT transporters have been identified and investigated for their anti-tumor activity in pre-clinical studies (131). For instance, BAY-876 and WZB117 GLUT-1 inhibitors have shown anti-proliferative effects in breast tumor cells (132).…”

Section: Targeting Molecular Mediators Of the Warburg Phenotypementioning

confidence: 99%

Lactate Metabolism and Immune Modulation in Breast Cancer: A Focused Review on Triple Negative Breast Tumors

Belič

Decock

2020

Front. Oncol.

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Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with poor prognosis, early recurrence, and the lack of durable chemotherapy responses and specific targeted treatments. The recent FDA approval for immune checkpoint inhibition in combination with nab-paclitaxel for the treatment of metastatic TNBC created opportunity to advocate for immunotherapy in TNBC patients. However, improving the current low response rates is vital. Most cancers, including TNBC tumors, display metabolic plasticity and undergo reprogramming into highly glycolytic tumors through the Warburg effect. Consequently, accumulation of the metabolic byproduct lactate and extracellular acidification is often observed in several solid tumors, thereby exacerbating tumor cell proliferation, metastasis, and angiogenesis. In this review, we focus on the role of lactate acidosis in the microenvironment of glycolytic breast tumors as a major driver for immune evasion with a special emphasis on TNBCs. In particular, we will discuss the role of lactate regulators such as glucose transporters, lactate dehydrogenases, and lactate transporters in modulating immune functionality and checkpoint expression in numerous immune cell types. This review aims to spark discussion on interventions targeting lactate acidosis in combination with immunotherapy to provide an effective means of improving response to immune checkpoint inhibitors in TNBC, in addition to highlighting challenges that may arise from TNBC tumor heterogeneity.

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“…In the past, direct supplementation with scFAs has been attempted, however, perhaps using lcFAs or polyunsaturated FAs would be more efficient in terms of ATP generation ( 26 ) ( Figure 2 ). An opposite approach would involve targeting Teff cells by inhibiting glucose uptake (via Glut transporters), glycolysis e.g., 2-DG), or inhibiting fatty acid uptake (CD36), fatty acid transport (a) or mitochondrial uptake (CPT1) ( 60 , 103 – 106 ).…”

Section: Translational Potential Of Treg Cell Metabolismmentioning

confidence: 99%

Metabolic Optimisation of Regulatory T Cells in Transplantation

et al. 2020

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Regulatory T (Treg) cells expressing the FOXP3 transcription factor are presently under investigation by many teams globally as a cellular therapy to induce tolerance in transplantation. This is primarily due to their immunosuppressive and homeostatic functions. Depending on the type of allograft, Treg cells will need to infiltrate and function in metabolically diverse microenvironments. This means that any resident and circulating Treg cells need to differentially adapt to counter acute or chronic allograft rejection. However, the links between Treg cell metabolism and function are still not entirely delineated. Current data suggest that Treg cells and their effector counterparts have different metabolite dependencies and metabolic programs. These properties could be exploited to optimize intragraft Treg cell function. In this review, we discuss the current paradigms regarding Treg cell metabolism and outline critical intracellular axes that link metabolism and function. Finally, we discuss how this knowledge could be clinically translated for the benefit of transplant patients.

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Small‐Molecule Inhibition of Glucose Transporters GLUT‐1–4

Cited by 67 publications

References 90 publications

In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy

In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy

Lactate Metabolism and Immune Modulation in Breast Cancer: A Focused Review on Triple Negative Breast Tumors

Metabolic Optimisation of Regulatory T Cells in Transplantation

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