Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt’s lymphoma anti-tumor activity

Curtis, Nicola J.; Mooney, Lorraine; Hopcroft, Lorna; Michopoulos, Filippos; Whalley, Nichola; Zhong, Haihong; Murray, Clare; Logié, Armelle; Revill, Mitchell; Byth, Kate; Benjamin, Amanda; Firth, Mike; Green, Stephen; Smith, Paul D.; Critchlow, Susan E.

doi:10.18632/oncotarget.18215

Cited by 118 publications

(131 citation statements)

References 47 publications

(56 reference statements)

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“…Public DLBCL gene expression data indicate that these tumours are among the lowest expressers of MCT4 mRNA [84], which would make them attractive targets for MCT1 inhibition. This notion has been confirmed in two studies on DLBCL cell lines [34,35] and on a cohort of DLBCL patients [35]. The two cell lines that were used in our study also exhibited high MCT1 and low MCT4 expression levels, but in our cohort of DLBCL patients a similar and high percentage of positive cases for both biomarkers was noted.…”

Section: Discussionsupporting

confidence: 87%

“…Consistent with a role of MCT1 in lactate transport to the extracellular milieu, extracellular lactate levels were found to be significantly diminished upon treatment with the MCT1 inhibitor. A potent disruption of lactate transport and anti-tumour activity of AZD3965 were also demonstrated by others, in monotherapy and in combination, in aggressive NHL models both in vitro and in vivo [34,35,81]. The efficacy of AZD3965 is currently explored in a clinical trial encompassing adult solid tumour and DLBCL patients (NCT01791595), and exciting preliminary results have been obtained [82].…”

Section: Discussionmentioning

confidence: 79%

“…Based on the above results on baseline levels of MCT in OZ and DOHH-2, it appears that these cells rely mainly on MCT1 for lactate transport across the plasma membrane. Therefore, we used AZD1365, a potent and selective inhibitor of MCT1 [34], to assess its effects on cell viability, apoptosis and lactate production. We found that the viability of both OZ and DOHH-2 cells was significantly compromised, although not completely inhibited, in a dose-and time-dependent manner, as shown in Fig.…”

Section: Effect Of Azd1365 In Lymphoma-derived Cell Linesmentioning

confidence: 99%

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Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma

et al. 2019

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Purpose Increased glycolytic activity with accumulation of extracellular lactate is regarded as a hallmark of cancer. In lymphomas, FDG-PET has undeniable diagnostic and prognostic value, corroborating that these tumours are avid for glucose. However, the role of glycolytic metabolism-related molecules in lymphoma is not well known. Here, we aimed to evaluate the clinical and prognostic significance of a panel of glycolytic metabolism-related molecules in primary non-Hodgkin lymphomas (NHL) and to test in vitro the putative therapeutic impact of lactate transport inhibition. Methods We assessed, by immunohistochemistry, the expression of the metabolism-related molecules MCT1, MCT2, MCT4, CD147, GLUT1, LDHA and CAIX in both tumour and stroma compartments of tissue sections obtained from 104 NHL patients. In addition, the lymphoma-derived cell lines OZ and DOHH-2 were used to evaluate the effect of AZD3965 on their viability and on apoptosis induction, as well as on extracellular lactate accumulation. Results We found that expression of MCT1 in the NHL tumour compartment was significantly associated with a poor clinicopathological profile. We also found that MCT4 and CAIX were present in the stromal compartment and correlated with an aggressive phenotype, while MCT1 was absent in this compartment. In addition, we found that AZD3965-mediated disruption of MCT1 activity led to inhibited NHL cell viability and extracellular lactate accumulation, while increasing apoptotic cell death.Conclusions Our results indicate that elevated glycolytic activity is associated with NHL aggressiveness, pointing at metabolic cooperation, mediated by MCT1 and MCT4, between tumour cells and their surrounding stroma. MCT1 may serve as a target to treat NHL (diffuse large B cell lymphoma) patients with high MCT1/low MCT4 expressing tumours. Further (pre-)clinical studies are required to allow the design of novel therapeutic strategies aimed at e.g. reprogramming the tumour microenvironment.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 79%

Section: Effect Of Azd1365 In Lymphoma-derived Cell Linesmentioning

confidence: 99%

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Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma

et al. 2019

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“…The MCT1 inhibitor AZD3965 is in early phase clinical trials (www.clinicaltrials.gov) with phase I expansion cohort enrichment for Burkitt lymphoma and diffuse large B cell lymphoma cases, given the promising pre-clinical results obtained with the drug in this setting. [11][12][13] Gaining an insight into the consequences of MCT1 inhibition on metabolism and tumour function as a whole is therefore necessary to (a) improve our understanding of the processes relevant to the drug's mechanism of action and (b) enable the discovery of pharmacodynamic (PD) biomarkers of target modulation.…”

Section: Introductionmentioning

confidence: 99%

Monocarboxylate transporter 1 blockade with AZD3965 inhibits lipid biosynthesis and increases tumour immune cell infiltration

et al. 2020

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BACKGROUND: Monocarboxylate transporter 1 (MCT1) is a regulator of cell metabolism and a therapeutic target for cancer treatment. Understanding the changes in tumour function accompanying MCT1 inhibition will better characterise the anti-tumour effects of MCT1 inhibitors, potentially enabling the identification of pharmacodynamic biomarkers for the clinical development of these agents. METHODS: We assessed the impact of the MCT1 inhibitor AZD3965 on tumour metabolism and immune cell infiltration as key determinants of tumour biological function in the MCT1-dependent Raji B cell lymphoma model. RESULTS: Treatment of Raji xenograft-bearing severe combined immunodeficiency mice with AZD3965 led to inhibition of tumour growth paralleled with a decrease in tumour choline, as detected by non-invasive in vivo proton nuclear magnetic resonance spectroscopy. This effect was attributed to inhibition of phosphocholine de novo synthesis following decreased choline kinase α protein and messenger RNA expression that correlated with the AZD3965-induced build-up in intracellular lactate. These changes were concomitant with increased tumour immune cell infiltration involving dendritic and natural killer cells. CONCLUSIONS: Our data provide new insights into the metabolic and cellular changes that occur in the tumour microenvironment following MCT1 blockade, which may contribute to the anti-tumour activity of AZD3965 and could have potential as pharmacodynamic biomarkers of MCT1 inhibition.

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“…Due to the significance of lactate in cancer progression, therapeutic agents targeting MCT1 could exert multiple anticancer influences. A first MCT1 inhibitor, AZD3965, is currently entering phase I/II clinical trials for advanced solid tumors (Curtis et al, 2017).…”

Section: Targeting Mcts and Glut1mentioning

confidence: 99%

New strategies for targeting glucose metabolism–mediated acidosis for colorectal cancer therapy

Wang

Yin

et al. 2018

Journal Cellular Physiology

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Colorectal cancer (CRC) is a heterogeneous group of diseases that are the result of abnormal glucose metabolism alterations with high lactate production by pyruvate to lactate conversion, which remodels acidosis and offers an evolutional advantage for tumor cells, even enhancing their aggressive phenotype. This review summarizes recent findings that involve multiple genes, molecules, and downstream signaling in the dysregulated glycolytic pathway, which can allow a tumor to initiate acid byproducts and to progress, thereby resulting in acidosis commonly found in the tumor microenvironment of CRC. Moreover, the relationship between CRC cells and the tumor acidic microenvironment, especially for regulating lactate production and lactate dehydrogenase A levels, is also discussed, as well as comprehensively defining different aspects of glycolytic pathways that affect cancer cell proliferation, invasion, and migration. Furthermore, this review concentrates on glucose metabolism-mediated transduction factors in CRC, which include acid-sensing ion channels, triosephosphate isomerase and key glycolysis-related enzymes that regulate glycolytic metabolites, coupled with the effect on tumor cell glycolysis as well as signaling pathways. In conclusion, glucose metabolism mediated by glycolytic pathways that are integral to tumor acidosis in CRC is demonstrated. Therefore, selective metabolic inhibitors or agents against these targets in glucose metabolism through glycolytic pathways may be clinically useful to regulate the tumor's acidic microenvironment for CRC treatment and to identify specific targets that regulate tumor acidosis through a cancer patient-personalized approach. Furthermore, strategies for modifying the metabolic processes that effectively inhibit cancer cell growth and tumor progression and activate potent anticancer effects may provide more effective antitumor prospects for CRC therapy.

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Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt’s lymphoma anti-tumor activity

Cited by 118 publications

References 47 publications

Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma

Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma

Monocarboxylate transporter 1 blockade with AZD3965 inhibits lipid biosynthesis and increases tumour immune cell infiltration

New strategies for targeting glucose metabolism–mediated acidosis for colorectal cancer therapy

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