Activity of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Small Cell Lung Cancer

Polański, Radosław; Hodgkinson, Cassandra L.; Fusi, Alberto; Nonaka, Daisuke; Priest, Lynsey; Kelly, Paul A.; Trapani, Francesca; Bishop, Paul; White, Anne; Critchlow, Susan E.; Smith, Paul D.; Blackhall, Fiona; Dive, Caroline; Morrow, Christopher J.

doi:10.1158/1078-0432.ccr-13-2270

Cited by 285 publications

(302 citation statements)

References 41 publications

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“…For example, MCT4-targeting siRNA has been reported to be effective at inhibiting renal cell carcinoma growth (51), and MCT4 expression in small cell lung cancer was found to confer resistance to specific MCT1 inhibitors (32). The candidate MCT4 ASOs developed in our laboratory could therefore be useful in multiple clinical settings, in particular if their efficacies can be improved by incorporating second-generation 2 0 -methoxyethyl modifications in their backbone (52).…”

Section: Discussionmentioning

confidence: 99%

TheMCT4Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer

Choi

Xue

et al. 2016

Clinical Cancer Research

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Purpose: The management of castration-resistant prostate cancer (CRPC) is a major challenge in the clinic. Androgen receptor signaling–directed strategies are not curative in CRPC therapy, and new strategies targeting alternative, key cancer properties are needed. Using reprogrammed glucose metabolism (aerobic glycolysis), cancer cells typically secrete excessive amounts of lactic acid into their microenvironment, promoting cancer development, survival, and progression. Cellular lactic acid secretion is thought to be predominantly mediated by MCT4, a plasma membrane transporter protein. As such, the MCT4 gene provides a unique, potential therapeutic target for cancer. Experimental Design: A tissue microarray of various Gleason grade human prostate cancers was stained for MCT4 protein. Specific, MCT4-targeting antisense oligonucleotides (MCT4 ASO) were designed and candidate MCT4 ASOs checked for effects on (i) MCT4 expression, lactic acid secretion/content, glucose consumption, glycolytic gene expression, and proliferation of human CRPC cells and (ii) growth of PC-3 tumors in nude mice. Results: Elevated MCT4 expression was associated with human CRPC and an earlier time to relapse. The treatment of PC-3, DU145, and C4-2 CRPC cultures with candidate MCT4 ASOs led to marked inhibition of MCT4 expression, lactic acid secretion, to increased intracellular lactic acid levels, and markedly reduced aerobic glycolysis and cell proliferation. Treatment of PC-3 tumor-bearing nude mice with the MCT4 ASOs markedly inhibited tumor growth without inducing major host toxicity. Conclusions: MCT4-targeting ASOs that inhibit lactic acid secretion may be useful for therapy of CRPC and other cancers, as they can interfere with reprogrammed energy metabolism of cancers, an emerging hallmark of cancer. Clin Cancer Res; 22(11); 2721–33. ©2016 AACR.

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Section: Discussionmentioning

confidence: 99%

TheMCT4Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer

Choi

Xue

et al. 2016

Clinical Cancer Research

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“…A second class of more potent MCT1/2 inhibitors has been designed, and one of these, AZD3965, is currently tested in phase I/II clinical trials for treatment of patients with advanced prostate cancer, gastric cancer, or diffuse large B‐cell lymphoma (NCT01791595). Preclinical studies in patients with small cell lung cancer indicate that this compound might also be effective in this cancer entity 96. Due to the overexpression of MCT4, especially in hypoxic tumor regions, it has long been searched for an MCT4‐specific inhibitor.…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Fisel

Schaeffeler

Schwab

2018

Clinical Translational Sci

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The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge.

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“…Here, we provided genetic evidence that targeting MCT1 and MCT4 reduced tumor growth and, if associated with the antidiabetic drugs phenformin/metformin (33), could, in a short tolerable therapeutic window, induce tumor cell death. Our optimism took off from our in vitro preliminary experiments on several cancer cell lines combining MCT1i and the novel specific MCT4 inhibitor in current development by AstraZeneca (46). Further experimentation with immune-competent mouse genetic cancer models and the MCT1/MCT4 inhibitors should demonstrate the benefit of this novel anticancer strategy.…”

Section: Inhibition Of Mcts Maintains Cell Survival By Reactivating Omentioning

confidence: 99%

Genetic Disruption of Lactate/H+ Symporters (MCTs) and Their Subunit CD147/BASIGIN Sensitizes Glycolytic Tumor Cells to Phenformin

et al. 2015

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Rapidly growing glycolytic tumors require energy and intracellular pH (pHi) homeostasis through the activity of two major monocarboxylate transporters, MCT1 and the hypoxia-inducible MCT4, in intimate association with the glycoprotein CD147/ BASIGIN (BSG). To further explore and validate the blockade of lactic acid export as an anticancer strategy, we disrupted, via zinc finger nucleases, MCT4 and BASIGIN genes in colon adenocarcinoma (LS174T) and glioblastoma (U87) human cell lines. First, we showed that homozygous loss of MCT4 dramatically sensitized cells to the MCT1 inhibitor AZD3965. Second, we demonstrated that knockout of BSG leads to a decrease in lactate transport activity of MCT1 and MCT4 by 10-and 6-fold, respectively. Consequently, cells accumulated an intracellular pool of lactic and pyruvic acids, magnified by the MCT1 inhibitor decreasing further pHi and glycolysis. As a result, we found that these glycolytic/MCT-deficient cells resumed growth by redirecting their metabolism toward OXPHOS. Third, we showed that in contrast with parental cells, BSG-null cells became highly sensitive to phenformin, an inhibitor of mitochondrial complex I. Phenformin addition to these MCT-disrupted cells in normoxic and hypoxic conditions induced a rapid drop in cellular ATP-inducing cell death by "metabolic catastrophe." Finally, xenograft analysis confirmed the deleterious tumor growth effect of MCT1/MCT4 ablation, an action enhanced by phenformin treatment. Collectively, these findings highlight that inhibition of the MCT/BSG complexes alone or in combination with phenformin provides an acute anticancer strategy to target highly glycolytic tumors. This genetic approach validates the anticancer potential of the MCT1 and MCT4 inhibitors in current development.

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Activity of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Small Cell Lung Cancer

Cited by 285 publications

References 41 publications

TheMCT4Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer

TheMCT4Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Genetic Disruption of Lactate/H+ Symporters (MCTs) and Their Subunit CD147/BASIGIN Sensitizes Glycolytic Tumor Cells to Phenformin

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