Pharmacological targeting of apelin impairs glioblastoma growth

Harford-Wright, Elizabeth; André-Grégoire, Gwennan; Jacobs, Kathryn; Treps, Lucas; Gonidec, Sophie Le; Leclair, Héloïse M; Gonzalez-Diest, Sara; Roux, Quentin de; Guilhot, François; Loussouarn, Delphine; Oliver, Lisa; Vallette, François M.; Foufelle, Fabienne; Valet, Philippe; Davenport, Anthony P.; Glen, Robert C.; Bidère, Nicolas; Gavard, Julie

doi:10.1093/brain/awx253

Cited by 79 publications

(144 citation statements)

References 40 publications

(60 reference statements)

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“…Decreased mitotic counts and Ki67 levels are established markers of better prognosis in breast cancer (van Diest et al , ). Finally, we used MM54, an Apelin antagonist with a K D of 3.4 μM and no reported agonistic activity, to block Apelin signaling (Macaluso et al , ; Harford‐Wright et al , ). Pharmacologic inhibition of Apelin signaling by MM54 had the same effect as genetically ablating Apelin expression, synergizing with sunitinib to reduce tumor progression (Fig E).…”

Section: Resultsmentioning

confidence: 99%

Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy

et al. 2019

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Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti‐angiogenic treatment has limited efficacy due to therapy‐induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy‐induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid‐derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti‐angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitor‐induced metastases, and high Apelin levels correlate with poor prognosis of anti‐angiogenic therapy patients. These data identify a druggable anti‐angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases.

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Section: Resultsmentioning

confidence: 99%

Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy

et al. 2019

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“…reported in metabolic diseases where it decreased adiposity, serum insulin and increased insulin sensitivity 16,17 ; and in renal diseases where it decreased acute renal injury and fibrosis 18 . It has recently emerged that apelin has pro-tumorigenic effects in various cancer models possibly by promoting angiogenesis and that inhibition of the apelin pathway was protective against tumour growth 14,19 . However, these beneficial effects of apelin peptides are limited by the rapid in vivo metabolism.…”

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confidence: 99%

Development and validation of an LC-MS/MS method for detection and quantification of in vivo derived metabolites of [Pyr1]apelin-13 in humans

Nyimanu

Kay

Šulentić

et al. 2019

Sci Rep

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[Pyr1]apelin-13 is the predominant apelin peptide isoform in the human cardiovascular system and plasma. To date, few studies have investigated [Pyr1]apelin-13 metabolism in vivo in rats with no studies examining its stability in humans. We therefore aimed to develop an LC-MS/MS method for detection and quantification of intact [Pyr1]apelin-13 and have used this method to identify the metabolites generated in vivo in humans. [Pyr1]apelin-13 (135 nmol/min) was infused into six healthy human volunteers for 120 minutes and blood collected at time 0 and 120 minutes after infusion. Plasma was extracted in the presence of guanidine hydrochloride and analysed by LC-MS/MS. Here we report a highly sensitive, robust and reproducible method for quantification of intact [Pyr1]apelin-13 and its metabolites in human plasma. Using this method, we showed that the circulating concentration of intact peptide was 58.3 ± 10.5 ng/ml after 120 minutes infusion. We demonstrated for the first time that in humans, [Pyr1]apelin-13 was cleaved from both termini but the C-terminal was more susceptible to cleavage. Consequently, of the metabolites identified, [Pyr1]apelin-13(1–12), [Pyr1]apelin-13(1–10) and [Pyr1]apelin-13(1–6) were the most abundant. These data suggest that apelin peptides designed for use as cardiovascular therapeutics, should include modifications that minimise C-terminal cleavage.

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“…Cell Culture, siRNA and DNA transfection, lentiviral transduction. GBM patient-derived cells with stem-like properties (GSCs) were isolated as previously described 15,54 .…”

Section: Methodsmentioning

confidence: 99%

“…GSCs are dispersed within tumors and methodically enriched in perivascular and hypoxic zones 11,12,13 . GSCs essentially received positive signals from endothelial cells and pericytes, such as ligand/receptor triggers of stemness pathways and adhesion components of the extracellular matrix 13,14,15,16,17 . They are also protected in rather unfavorable conditions where their stemness traits resist hypoxic stress, acidification, and nutrient deprivation 11,12,18 .…”

Section: Introductionmentioning

confidence: 99%

Control of the Endo-Lysosome Homeostasis by the Paracaspase MALT1 regulates Glioma Cell Survival

Jacobs

André-Grégoire

Maghe

et al. 2019

Preprint

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Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem-like cells (GSC), which constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa-associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor-mediated NF-κB activation and B-cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient-derived stem-like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo-lysosome abundance, impaired autophagic flux, and culminates in lysosomalmediated death, concomitantly with mTOR inactivation and dispersion from lysosomes.These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.

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Pharmacological targeting of apelin impairs glioblastoma growth

Cited by 79 publications

References 40 publications

Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy

Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy

Development and validation of an LC-MS/MS method for detection and quantification of in vivo derived metabolites of [Pyr1]apelin-13 in humans

Control of the Endo-Lysosome Homeostasis by the Paracaspase MALT1 regulates Glioma Cell Survival

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