Genetic biomarkers of drug response for small-molecule therapeutics targeting the RTK/Ras/PI3K, p53 or Rb pathway in glioblastoma

Venkatesan, S.; Lamfers, Martine L.M.; Dirven, Clemens M.F.; Leenstra, Sieger

doi:10.2217/cns-2015-0005

Cited by 31 publications

(25 citation statements)

References 116 publications

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“…In the clinic, mutations of p53 or Rb proteins and the components of their pathways are found in the human glioblastoma. 30,31 BP/LPPC contributed to a rapid increase in the p53 protein level that caused down-regulation of cell division. BP/LPPC also regulated p21 mediated p53dependent G1 growth arrest by binding to cyclin D1/ CDK4, or the cyclin D1/CDK6 complex, preventing the phosphorylation of the retinoblastoma (Rb) protein and resulting in G1 arrest.…”

Section: Discussionmentioning

confidence: 99%

Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma

Lin¹,

Huang²,

Chang³

et al. 2020

IJN

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Background: n-Butylidenephthalide (BP) has anti-tumor effects on glioblastoma. However, the limitation of BP for clinical application is its unstable structure. A polycationic liposomal polyethylenimine (PEI) and polyethylene glycol (PEG) complex (LPPC) has been developed to encapsulate BP for drug structure protection. The purpose of this study was to investigate the anti-cancer effects of the BP/LPPC complex on glioblastoma in vitro and in vivo. Methods: DBTRG-05MG tumor bearing xenograft mice were treated with BP and BP/ LPPC and then their tumor sizes, survival, drug biodistribution were measured. RG2 tumor bearing F344 rats also treated with BP and BP/LPPC and then their tumor sizes by magnetic resonance imaging for evaluation blood-brain barrier (BBB) across and drug therapeutic effects. After treated with BP/LPPC in vitro, cell uptake, cell cycle and apoptotic regulators were analyzed for evaluation the therapeutic mechanism. Results: In athymic mice, BP/LPPC could efficiently suppress tumor growth and prolong survival. In F334 rats, BP/LPPC crossed the BBB and led to tumor shrinkage. BP/LPPC promoted cell cycle arrest at the G 0 /G 1 phase and triggered the extrinsic and intrinsic cell apoptosis pathways resulting cell death. BP/LPPC also efficiently suppressed VEGF, VEGFR1, VEGFR2, MMP2 and MMP9 expression. Conclusion: BP/LPPC was rapidly and efficiently transported to the tumor area across the BBB and induced cell apoptosis, anti-angiogenetic and anti-metastatic effects in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma

Lin¹,

Huang²,

Chang³

et al. 2020

IJN

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“…ALK_DN.V1_DN are genes downregulated upon knockdown of the oncogene, anaplastic lymphoma kinase (ALK) . Mutated TP53, hedgehog, and ALK have been noted to regulate the development and progression of glioma . Therefore, CMG2 might orchestrate these signaling pathways to regulate the growth of glioma cells.…”

Section: Discussionmentioning

confidence: 99%

Capillary morphogenesis protein 2 is a novel prognostic biomarker and plays oncogenic roles in glioma

Tan

Liu

Zhang

et al. 2018

The Journal of Pathology

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Capillary morphogenesis protein 2 (CMG2) was originally identified through its participation in capillary morphogenesis, and subsequently identified as the second receptor for anthrax toxin (ANTXR2). Although tumor-associated functions of CMG2 have also been reported, the clinical significance and functional mechanism of CMG2 in glioma remain to be elucidated. We assessed the clinicopathological relevance of CMG2 in a cohort of 48 glioma patients as well as through public glioma databases, and explored the function of CMG2 using glioblastoma (GBM) models in vitro and in vivo. CMG2 overexpression was associated with increased tumor grade and poor patient survival. CMG2 promoted G2/M-phase transition during the cell cycle of GBM cells in vitro and contributed to tumor growth in vivo. We also observed that CMG2 is implicated in the activation of extracellular signal-regulated kinases (ERKs), epithelial-mesenchymal transition (EMT), migration, and invasion in GBM cells. Transcriptomic analysis of GBM cells with or without CMG2 overexpression indicated that a panel of oncogenic signaling pathways was altered with CMG2 upregulation, implying that CMG2 might orchestrate these signaling pathways to regulate the growth of GBM cells. Yes-associated protein 1 (YAP1) activity was enhanced by CMG2 overexpression but suppressed with CMG2 deficiency. Since YAP1 is critically implicated in GBM, the oncogenic roles of CMG2 in GBM cells might thus be mediated, at least partially, by YAP1. Altogether, CMG2 functioned as an oncogene in glioma cells and is a potential prognostic biomarker or therapeutic target for the clinical treatment of glioma. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…GB is characterized by the deregulation of many key signaling pathways involving growth, proliferation, survival, and apoptosis, such as p53, pRB, EGFR, PI3K, STAT3 or WNT 32-33 . WNT signaling has long been suggested as a hallmark in gliomagenesis associated with the proliferation of stem-like cells in human GBs 34 .…”

Section: Resultsmentioning

confidence: 99%

WNT vampirization by glioblastoma leads to tumor growth and neurodegeneration

Portela

Venkataramani

Fahey-Lozano

et al. 2018

Preprint

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22Glioblastoma (GB) is the most lethal brain tumor due to its high proliferation, 23 aggressiveness, infiltration capacity and resilience to current treatments. Activation of 24 the Wingless-related-integration-site (WNT) pathway is associated with a bad 25 prognosis. Using Drosophila and primary xenograft models of human GB, we describe 26 a mechanism that leads to the activation of WNT signaling [Wingless (Wg) in 27 Drosophila] in tumor cells. GB cells display a network of tumor microtubes (TMs) which 28 enwraps neurons, accumulates Wg receptor Frizzled1 (Fz1), and, thereby, actively 29 depletes Wg from the neurons. Consequently, GB cells proliferate due to β-catenin 30 activation, and neurons degenerate due to Wg signaling extinction. This novel view 31 explains both neuron-dependent tumor progression, and also the neural decay 32 associated with GB. 33 Keywords 34Neuron, Glia, Cancer, wingless, Frizzled, Glioblastoma, 35 Cytoneme, Wg-depletion. 36 37The WNT canonical pathway is activated upon the ligand "Wingless-related integration 48 site" (WNT) binding to specific receptors (LRPs and FZD) in the plasma membrane. As 49 a consequence, the destruction complex (APC and Axin) is inactivated and β-catenin 50 (armadillo in Drosophila) is released. Further, β-catenin translocates into the cell 51 nucleus where it promotes the expression of target genes (i.e. Cyclin D1 and Myc) 7-8 . 52The WNT pathway is conserved through metazoans and it plays a central role in brain 53 development 9 , adult neuronal physiology 10 and synaptogenesis 11 . Perturbations in 54WNT signaling are associated with neural deficits, Alzheimer´s disease and brain 55 cancer, most notably GB 12 . WNT and FZD signaling can be deregulated in 56 glioblastoma 13-14 (reviewed in 15 ). In particular, one of the hallmarks of bad prognosis is 57 the accumulation of ß-catenin in tumoral cells [16][17] , indicating an activation of WNT/FZD 58 pathway 18 . 59 GB cells extend ultra-long membrane protrusions that interconnect tumor cells 19 . 60These tumor microtubes (TMs) are associated with the worst prognosis in molecular 61 subtypes of human gliomas. TMs contribute to invasion and proliferation, resulting in 62 effective brain colonization by GB cells. Moreover, TMs constitute a multicellular 63 network that connects GB cells over long distances, a feature that likely provides 64 resistance against radiotherapy, chemotherapy and surgery [19][20] . Considering the many 65 cytological similarities of TMs and tunneling nanotubes (TNTs) 21 , it seems that TMs in 66 aggressive gliomas are the in vivo correlate of TNTs described in cell culture. In 67 addition, TMs seem akin to a basic mechanism of cell-cell connection and molecular 68 communication called "cytonemes" in Drosophila 22 . Growth Associated Protein-43 69 (GAP43) is essential for the development of TMs and, thus, the tumor cell network 70 which is associated with GB progression 19 . However, many aspects of this 71 paradigmatic finding in glioma biology are still unexplored, including its i...

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Genetic biomarkers of drug response for small-molecule therapeutics targeting the RTK/Ras/PI3K, p53 or Rb pathway in glioblastoma

Cited by 31 publications

References 116 publications

<p>Encapsulated <em>n</em>-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma</p>

<p>Encapsulated <em>n</em>-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma</p>

Capillary morphogenesis protein 2 is a novel prognostic biomarker and plays oncogenic roles in glioma

WNT vampirization by glioblastoma leads to tumor growth and neurodegeneration

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