Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since tumors cannot grow or spread without forming new blood vessels, inhibiting angiogenesis is an excellent approach for the treatment of cancer. Further, inhibitors of angiogenesis have mild side effects since they act on endothelial cells, which eliminate the possibility of developing resistance or tolerance in tumor cells, unlike that seen with chemotherapy drugs. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab acts by preventing new blood vessel formation in solid tumors and is approved by FDA to treat colorectal, lung, breast, glioblastoma and kidney cancers. The registration of this drug and its ongoing success in the clinic has validated the targeting of angiogenesis as an important approach to the treatment of solid tumors. Apelin is a novel angiogenic factor and recent studies indicate that apelin promotes angiogenesis, lymphangiogenesis and tumor growth in vivo and the angiogenic potential of apelin is similar to that of VEGF. Also, apelin expression is upregulated and has been shown to be associated with clinical outcome in certain human cancers. Thus, inhibition of apelin activity might lead to a new class of anti-angiogenesis drugs which should be more efficacious than those currently on the market due to their ability to be both anti-angiogenic as well as anti-lymphangiogenic. There are very few patents on the angiogenic effects of apelin and this review article focuses on these patented claims related to inhibiting apelin signaling and sheds more light on how blocking apelin signaling might open doors to a new class of angiogenic inhibitors.
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PMID:Emerging role of apelin as a therapeutic target in cancer: a patent review. 2161 76

Glioblastoma are highly aggressive brain tumours that are associated with an extremely poor prognosis. Within these tumours exists a subpopulation of highly plastic self-renewing cancer cells that retain the ability to expand ex vivo as tumourspheres, induce tumour growth in mice, and have been implicated in radio- and chemo-resistance. Although their identity and fate are regulated by external cues emanating from endothelial cells, the nature of such signals remains unknown. Here, we used a mass spectrometry proteomic approach to characterize the factors released by brain endothelial cells. We report the identification of the vasoactive peptide apelin as a central regulator for endothelial-mediated maintenance of glioblastoma patient-derived cells with stem-like properties. Genetic and pharmacological targeting of apelin cognate receptor abrogates apelin- and endothelial-mediated expansion of glioblastoma patient-derived cells with stem-like properties in vitro and suppresses tumour growth in vivo. Functionally, selective competitive antagonists of apelin receptor were shown to be safe and effective in reducing tumour expansion and lengthening the survival of intracranially xenografted mice. Therefore, the apelin/apelin receptor signalling nexus may operate as a paracrine signal that sustains tumour cell expansion and progression, suggesting that apelin is a druggable factor in glioblastoma.
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PMID:Pharmacological targeting of apelin impairs glioblastoma growth. 2905 91

Glioblastoma multiforme are mortifying brain tumors that contain a subpopulation of tumor cells with stem-like properties, termed as glioblastoma stem-like cells (GSCs). These GSCs constitute an autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. A new therapeutic strategy would consist of targeting the GSC population. The GSCs are situated in perivascular niches, closely associated with brain microvascular endothelial cells thereby involved in bidirectional molecular and cellular interactions. In this scenario, the endothelium not only supplies oxygen and necessary nutrients but also seeds a protective microenvironment for tumor growth. Although GSC fate, plasticity, and survival are regulated by external cues emanating from endothelial cells, the nature of such angiocrine signals remains unknown. Our laboratory conclusively demonstrated that brain endothelial cells positively control the expansion of GSCs.1 Notably, we found that GSCs are addicted to the hormonal peptide apelin (APLN) secreted by surrounding endothelial cells, and identified the APLN/APLNR nexus as a promising druggable network in glioblastoma.
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PMID:Apelin, the Devil Inside Brain Tumors. 2953 51

Antiangiogenic therapy of glioblastoma (GBM) with bevacizumab, a VEGFA-blocking antibody, may accelerate tumor cell invasion and induce alternative angiogenic pathways. Here we investigate the roles of the proangiogenic apelin receptor APLNR and its cognate ligand apelin in VEGFA/VEGFR2 antiangiogenic therapy against distinct subtypes of GBM. In proneural GBM, apelin levels were downregulated by VEGFA or VEGFR2 blockade. A central role for apelin/APLNR in controlling GBM vascularization was corroborated in a serial implantation model of the angiogenic switch that occurs in human GBM. Apelin and APLNR are broadly expressed in human GBM, and knockdown or knockout of APLN in orthotopic models of proneural or classical GBM subtypes significantly reduced GBM vascularization compared with controls. However, reduction in apelin expression led to accelerated GBM cell invasion. Analysis of stereotactic GBM biopsies from patients as well as from in vitro and in vivo experiments revealed increased dissemination of APLNR-positive tumor cells when apelin levels were reduced. Application of apelin-F13A, a mutant APLNR ligand, blocked tumor angiogenesis and GBM cell invasion. Furthermore, cotargeting VEGFR2 and APLNR synergistically improved survival of mice bearing proneural GBM. In summary, we show that apelin/APLNR signaling controls GBM angiogenesis and invasion and that both pathologic features are blunted by apelin-F13A. We suggest that apelin-F13A can improve the efficiency and reduce the side effects of established antiangiogenic treatments for distinct GBM subtypes. SIGNIFICANCE: Pharmacologic targeting of the APLNR acts synergistically with established antiangiogenic treatments in glioblastoma and blunts therapy resistance to current strategies for antiangiogenesis.See related commentary by Amoozgar et al., p. 2104.
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PMID:Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma. 3104 29

Glioblastoma (GBM) is the most common and deadliest primary adult brain tumor. Invasion, resistance to therapy, and tumor recurrence in GBM can be attributed in part to brain tumor-initiating cells (BTICs). BTICs isolated from various patient-derived xenografts showed high expression of the poorly characterized Apelin early ligand A (APELA) gene. Although originally considered to be a non-coding gene, the APELA gene encodes a protein that binds to the Apelin receptor and promotes the growth of human embryonic stem cells and the formation of the embryonic vasculature. We found that both APELA mRNA and protein are expressed at high levels in a subset of brain tumor patients, and that APELA is also expressed in putative stem cell niche in GBM tumor tissue. Analysis of APELA and the Apelin receptor gene expression in brain tumor datasets showed that high APELA expression was associated with poor patient survival in both glioma and glioblastoma, and APELA expression correlated with glioma grade. In contrast, gene expression of the Apelin receptor or Apelin was not found to be associated with patient survival, or glioma grade. Consequently, APELA may play an important role in glioblastoma tumorigenesis and may be a future therapeutic target.
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PMID:APELA Expression in Glioma, and Its Association with Patient Survival and Tumor Grade. 3091 21

The limited efficacy of current antiangiogenic therapies calls for a better understanding of the specific resistance mechanisms in glioblastoma (GBM) and the urgent development of new therapeutic strategies targeting these pathways. In this issue of Cancer Research, Mastrella and colleagues reported that expression of the proangiogenic peptide apelin (APLN) was decreased and GBM cell invasion was increased after anti-VEGF therapy in preclinical models of GBM. Using the mutant form of the natural apelin-13 peptide, the authors showed reduction of both angiogenesis and invasion in the GBM models, and further increased the efficacy of anti-VEGF therapy. VEGF blockade is still widely used as salvage therapy for recurrent GBM, therefore these intriguing results have potential translational implications as they point to a potential new strategy to overcome VEGF blockade resistance; however, they also raise important questions for the clinical translation of this strategy, and its impact on antitumor responses, in particular immune responses.See related article by Mastrella et al., p. 2298.
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PMID:Role of Apelin in Glioblastoma Vascularization and Invasion after Anti-VEGF Therapy: What Is the Impact on the Immune System? 3071 58

Adipose tissue is an important source of adipokines involved in anti- and pro-inflammatory effects. Their involvement in certain cancers such as breast and colon cancer is known but in gliomas it remains unexplored till date. The aim of this study was to assess the status of adipokines as prognostic markers of gliomas (low grade gliomas [LGG] and glioblastoma mutiforme [GBM]). Expression status (messenger RNA [mRNA]), overall survival (OS) and disease-free survival (DFS) was identified using gene expression profiling interactive analysis server. Clinicopathological analysis and correlation between different adipokines was performed using Xena server. Protein expression status was analyzed using tissue sections from the Human Protein Atlas. Out of 11 adipokines studied visfatin (NAMPT), apelin (APLN), granulin (GRN), serpin peptidase inhibitor/plasminogen activator inhibitor type 1 (PAI-1) member 1 (SERPINE1), and chemokine (C-C motif) ligand 2 (CCL2) mRNA levels were significantly upregulated in both LGG and GBM. Interleukin 6 (IL6) mRNA was found be significantly upregulated only in GBM. NAMPT, GRN, SERPINE1, and IL6 showed reduced OS as well as worst DFS for patients having higher mRNA expression in LGG. Increased expression of CCL2 showed worst OS in LGG patients while resistin (RETN) and GRN showed the worst OS in GBM patients. Higher expression of RETN, GRN, IL6, SERPINE1, and CCL2 were found to be positively correlated with shorter DFS in GBM. In the clinicopathological analysis, NAMPT, GRN, IL6, SERPINE1, and CCL2 expressions were significantly associated between the neoplasm histological G2 and G3 grades. Furthermore, expression of NAMPT, GRN, tumor necrosis factor, IL6, SERPINE1, and CCL2 were significantly associated with histological type in LGG patients. NAMPT, GRN, SERPINE1, CCL2, and RETN expression were found to be correlated with each other in gliomas. Finally, NAMPT, GRN, and SERPINE1 were also found to be upregulated using immunohistochemistry in a lower grade and high grade gliomas as compared to normal cells. In conclusion, we have identified key adipokines, namely NAMPT, GRN, and SERPINE1 as potential diagnostic and prognostic markers that might be instrumental in the development and progression of gliomas.
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PMID:NAMPT, GRN, and SERPINE1 signature as predictor of disease progression and survival in gliomas. 3171 Jan 21

Glioblastoma (GBM) present with an abundant and aberrant tumor neo-vasculature. While rapid growth of solid tumors depends on the initiation of tumor angiogenesis, GBM also progress by infiltrative growth and vascular co-option. The angiogenic factor apelin (APLN) and its receptor (APLNR) are upregulated in GBM patient samples as compared to normal brain tissue. Here, we studied the role of apelin/APLNR signaling in GBM angiogenesis and growth. By functional analysis of apelin in orthotopic GBM mouse models, we found that apelin/APLNR signaling is required for in vivo tumor angiogenesis. Knockdown of tumor cell-derived APLN massively reduced the tumor vasculature. Additional loss of the apelin signal in endothelial tip cells using the APLN-knockout (KO) mouse led to a further reduction of GBM angiogenesis. Direct infusion of the bioactive peptide apelin-13 rescued the vascular loss-of-function phenotype specifically. In addition, APLN depletion massively reduced angiogenesis-dependent tumor growth. Consequently, survival of GBM-bearing mice was significantly increased when APLN expression was missing in the brain tumor microenvironment. Thus, we suggest that targeting vascular apelin may serve as an alternative strategy for anti-angiogenesis in GBM.
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PMID:Apelin Controls Angiogenesis-Dependent Glioblastoma Growth. 3254 80