Dual functionalized brain-targeting nanoinhibitors restrain temozolomide-resistant glioma via attenuating EGFR and MET signaling pathways

Meng, Xiangqi; Zhao, Yu; Han, Bo; Zha, Caijun; Zhang, Yangong; Li, Ziwei; Wu, Pengfei; Qi, Tengfei; Jiang, Chuanlu; Liu, Yang

doi:10.1038/s41467-019-14036-x

Cited by 93 publications

(59 citation statements)

References 71 publications

(103 reference statements)

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“…The physiological function of EGFR is to modify epithelial tissue development and angiogenesis (Sigismund et al, 2018). EGFR amplification is highly related to TMZ resistance in glioma (Ma et al, 2019;Meng et al, 2020). Combined 7 + /10− has been described as a prognostic hallmark and has a strong correlation with the NF-kB complex and Akt pathway (Baysan et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Characteristics of IDH-Wild Type Glioma Subgroups Highlight the Biological Processes Underlying Heterogeneity of IDH-Wild Type WHO Grade IV Gliomas

Chang

Pang

et al. 2020

Front. Cell Dev. Biol.

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Isocitric dehydrogenase (IDH)-wild type diffuse gliomas, which have a poorer prognosis than their IDH-mutant counterparts, are also accompanied with high heterogeneity. Here, we aimed to identify the key biological processes associated with the three groups of IDH-wild type diffuse gliomas in 323 patients. By The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) update 3 recommendation, the three groups are Group A, diffuse astrocytic glioma, World Health Organization (WHO) grade II/III; Group B, diffuse astrocytic glioma, with one (or more) of the three genetic alterations: TERT promoter mutation, EGFR gene amplification, gain of chromosome 7 combined with loss of chromosome 10, WHO grade IV; and Group C, glioblastoma, WHO grade IV. Consistent with their histologic and genetic molecular features, we successfully identified that biological activities associated with "cell cycle" and "cell mitosis" are significantly elevated in Group B compared with Group A; microenvironment-related hallmarks "angiogenesis" and "hypoxia," and biological processes of "extracellular matrix," "immune response," and "positive regulation of transcriptional activities" were more enriched in Group C than Group B. We also constructed a nine-gene signature from differentially expressed genes among the three groups to further stratify the WHO grade IV gliomas (Groups B and C) whose survival cannot be clearly stratified by current classification systems. This signature was an independent prognosis factor for WHO grade IV gliomas and had better prognostic value than other known factors in both training and validation dataset. In addition, the signature risk score was positively correlated with the amount of infiltrated immune cells, expression of immune checkpoints, and the genes enriched in biological processes of "immune response," "cell cycle," and "extracellular matrix." The bioinformatic analysis results were also validated by immunohistochemistry and patient-derived cell

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Section: Discussionmentioning

confidence: 99%

Transcriptional Characteristics of IDH-Wild Type Glioma Subgroups Highlight the Biological Processes Underlying Heterogeneity of IDH-Wild Type WHO Grade IV Gliomas

Chang

Pang

et al. 2020

Front. Cell Dev. Biol.

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“…Although PLK2-Notchtargeted monotherapy seems to be promising, a better accomplishment is to combine Notch inhibitors with other molecules or chemotherapeutic agents like bevacizumab and TMZ, respectively. Additionally, Meng et al (58) found the simultaneous inhibition of EGFR and MET signaling by a novel nanoparticle enhanced TMZ chemosensitivity in TMZ-resistant cell lines, indicating the signi cance of targeting different pathways that contribute to chemoresistance. Although the underlying roles of PLK2 in chemoresistance are well discussed in this study, additional molecular biological investigations are still required for evaluating the clinical signi cance of PLK2 in chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of Notch signaling

Alafate

et al. 2020

Preprint

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BackgroundGlioblastoma (GBM) is a lethal type of primary brain tumor with a median survival less than 15 months. Despite the recent improvements of comprehensive strategies, the outcomes for GBM patients remain dismal. Accumulating evidence indicates that rapid acquired chemoresistance is the major cause of GBM recurrence thus leads to worse clinical outcomes. Therefore, developing novel biomarkers and therapeutic targets for chemoresistant GBM is crucial for long-term cures. MethodsTranscriptomic profiles of glioblastoma were downloaded from gene expression omnibus (GEO) and TCGA database. Differentially expressed genes were analyzed and candidate gene PLK2 was selected for subsequent validation. Clinical samples and corresponding data were collected from our center and measured using immunohistochemistry analysis. Lentiviral transduction and in vivo xenograft transplantation were used to validate the bioinformatic findings. GSEA analyses were conducted to identify potential signaling pathways related to PLK2 expression and further confirmed by in vitro mechanistic assays. ResultsIn this study, we identified PLK2 as an extremely suppressed kinase-encoding gene in GBM samples, particularly in therapy resistant GBM. Additionally, reduced PLK2 expression implied poor prognosis and TMZ resistance in GBM patients. Functionally, up-regulated PLK2 attenuated cell proliferation, migration, invasion, and tumorigenesis of GBM cells. Besides, exogenous overexpression of PLK2 reduced acquired TMZ resistance of GBM cells. Furthermore, bioinformatics analysis indicated that PLK2 was negatively correlated with Notch signaling pathway in GBM. Mechanically, loss of PLK2 activated Notch pathway through negative transcriptional regulation of HES1 and degradation of Notch1.ConclusionLoss of PLK2 enhances aggressive biological behavior of GBM through activation of Notch signaling, indicating that PLK2 could be a prognostic biomarker and potential therapeutic target for chemoresistant GBM.

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“…For non-invasive tumor-targeted delivery, nanomedicines could be a possible solution [ 53 , 54 ]. Recent preclinical studies in glioma models present nanoparticles developed using poly-MPC coating as an effective way to cross BBB [ 55 , 56 ]. Nano-formulations of PARPi have already been reported, although none with radiotracers.…”

Section: Future Prospects and Conclusionmentioning

confidence: 99%

Advancements in PARP1 Targeted Nuclear Imaging and Theranostic Probes

Sankaranarayanan

Kossatz

Weber

et al. 2020

JCM

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The central paradigm of novel therapeutic approaches in cancer therapy is identifying and targeting molecular biomarkers. One such target is the nuclear DNA repair enzyme Poly-(ADP ribose) polymerase 1 (PARP1). Sensitivity to PARP inhibition in certain cancers such as gBRCAmut breast and ovarian cancers has led to its exploitation as a target. The overexpression of PARP1 in several types of cancer further evoked interest in its use as an imaging target. While PARP1-targeted inhibitors have fast developed and approved in this past decade, determination of PARP1 expression might help to predict the response to PARP inhibitor treatment. This has the potential of improving prognosis and moving towards tailored therapy options and/or dosages. This review summarizes the recent pre-clinical advancements in imaging and theranostic PARP1 targeted tracers. To assess PARP1 levels, several imaging probes with fluorescent or beta/gamma emitting radionuclides have been proposed and three have advanced to ongoing clinical evaluation. Apart from its diagnostic value in detection of primary tumors as well as metastases, this shall also help in delivering therapeutic radionuclides to PARP1 overexpressing tumors. Henceforth nuclear medicine has now advanced towards conjugating theranostic radionuclides to PARP1 inhibitors. This paves the way for a future of PARP1-targeted theranostics and personalized therapy.

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Dual functionalized brain-targeting nanoinhibitors restrain temozolomide-resistant glioma via attenuating EGFR and MET signaling pathways

Cited by 93 publications

References 71 publications

Transcriptional Characteristics of IDH-Wild Type Glioma Subgroups Highlight the Biological Processes Underlying Heterogeneity of IDH-Wild Type WHO Grade IV Gliomas

Transcriptional Characteristics of IDH-Wild Type Glioma Subgroups Highlight the Biological Processes Underlying Heterogeneity of IDH-Wild Type WHO Grade IV Gliomas

Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of Notch signaling

Advancements in PARP1 Targeted Nuclear Imaging and Theranostic Probes

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