GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer

Wu, Qin; Ba-Alawi, Wail; Deblois, Geneviève; Cruickshank, Jennifer; Duan, Shili; Lima‐Fernandes, Evelyne; Haight, Jillian; Tonekaboni, Seyed Ali Madani; Fortier, Anne-Marie; Kuasne, Hellen; McKee, Trevor D.; Mahmoud, Hassan; Kushida, Michelle; Cameron, Sarina; Dogan-Artun, Nergiz; Chen, Wenjun; Nie, Yan; Zhang, Lan-Xin; Vellanki, Ravi N.; Zhou, Stanley; Prinos, Panagiotis; Wouters, Bradly G.; Dirks, Peter B.; Done, Susan J.; Park, Morag; Cescon, David W.; Haibe‐Kains, Benjamin; Lupien, Mathieu; Arrowsmith, C.H.

doi:10.1038/s41467-020-18020-8

Cited by 182 publications

(122 citation statements)

References 74 publications

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“… 33 Among the reported GLUT inhibitors, BAY-876 is the only inhibitor that is both highly potent and selective for GLUT1 over other glucose transporters, including WZB-117. 34 Thus, it is likely that the results show a difference in selectivity to Glut1 in our study. While it is still unclear to evaluate a survival benefit to BAY-876 in this study, scaled-up pharmacological studies, including those to evaluate other Glut1 inhibitors, are needed.…”

Section: Discussionmentioning

confidence: 63%

Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment

Miyai

Kanayama

Hyodo

et al. 2020

Neuro-Oncology Advances

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Background Gliomas typically escape surgical resection and recur due to their “diffusion invasion” phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed two key features of the “diffuse invasion” phenotype, designated the Scherer's secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown. Methods We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffusion invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients. Results Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, i.e., attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients. Conclusions Targeting the transporter Glut1 suppresses the unique phenotype, “diffuse invasion” in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.

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Section: Discussionmentioning

confidence: 63%

Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment

Miyai

Kanayama

Hyodo

et al. 2020

Neuro-Oncology Advances

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“…Lastly, well-designed interventional studies examining intra-tumoral or systemic biomarkers to enable stratification of TNBC patients that may benefit from combining immunotherapy with anti-metabolic strategies are essential. Such biomarkers could include genetic mutations or variants that have been associated with metabolic reprogramming in TNBC (166) such as mutant p53 (19), BRCA1 mutations (167,168), c-Myc amplification (169), and Rb expression (133). Notably, investigation of congenital lactic acidosis has identified distinct genetic variants that result in defective mitochondrial function and drive the pathogenesis of the disease (170) and hence, assessment of the effect of these genetic alterations on tumor metabolic phenotype would be of interest in the search for prognostic biomarkers.…”

Section: Resultsmentioning

confidence: 99%

“…For instance, BAY-876 and WZB117 GLUT-1 inhibitors have shown anti-proliferative effects in breast tumor cells (132). In particular, a subset of TNBC tumors expressing the retinoblastoma (Rb) tumor suppressor with high glycolytic activity and low OXPHOS are sensitive to GLUT1 inhibition with BAY-876 (133). Since GLUTs are ubiquitously expressed, the impact of their inhibition at peripheral organs still needs to be well documented.…”

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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“…Retinoblastoma protein (RB1) and TP53 are tumor suppressor genes, which could avoid tumoral cell growth by promoting cancer cell death. The inactivation of RB1 is frequently assessed in triple-negative BC and is linked to sensitivity to many cancer drugs, including TOP1 inhibitors [46,47].…”

Section: Discussionmentioning

confidence: 99%

Patient-Specific Network for Personalized Breast Cancer Therapy with Multi-Omics Data

Cava

Sabetian

Castiglioni

2021

Entropy

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The development of new computational approaches that are able to design the correct personalized drugs is the crucial therapeutic issue in cancer research. However, tumor heterogeneity is the main obstacle to developing patient-specific single drugs or combinations of drugs that already exist in clinics. In this study, we developed a computational approach that integrates copy number alteration, gene expression, and a protein interaction network of 73 basal breast cancer samples. 2509 prognostic genes harboring a copy number alteration were identified using survival analysis, and a protein–protein interaction network considering the direct interactions was created. Each patient was described by a specific combination of seven altered hub proteins that fully characterize the 73 basal breast cancer patients. We suggested the optimal combination therapy for each patient considering drug–protein interactions. Our approach is able to confirm well-known cancer related genes and suggest novel potential drug target genes. In conclusion, we presented a new computational approach in breast cancer to deal with the intra-tumor heterogeneity towards personalized cancer therapy.

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GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer

Cited by 182 publications

References 74 publications

Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment

Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment

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

Patient-Specific Network for Personalized Breast Cancer Therapy with Multi-Omics Data

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