Differentiation of glioblastoma multiforme stem-like cells leads to downregulation of EGFR and EGFRvIII and decreased tumorigenic and stem-like cell potential

Stockhausen, Marie-Thérése; Kristoffersen, Karina; Stobbe, Louise; Poulsen, Hans Skovgaard

doi:10.4161/cbt.26736

Cited by 33 publications

(36 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, both PC4 loading and the difference spectrum showed a decrease of the spectral band centered at 965 cm −1 , assigned to the symmetric stretching mode of di-anionic phosphate mono-esters of phosphorylated proteins [26] and therefore pointing to a decrease in the level of phosphorylated proteins in the differentiated glioma cells. This is in line with the fact that glioma stem cells express high levels of protein kinases, for example EGFR, EGFRvIII, which decrease during the differentiation [27]. Down-regulation of kinase inhibitors (i.e.…”

Section: Ftir Microspectroscopy Measurements Reveal Changes In Lipidsmentioning

confidence: 85%

Fourier transform infrared microspectroscopy reveals biochemical changes associated with glioma stem cell differentiation

Kenig

Bedolla

Birarda

et al. 2015

Biophysical Chemistry

View full text Add to dashboard Cite

Section: Ftir Microspectroscopy Measurements Reveal Changes In Lipidsmentioning

confidence: 85%

Fourier transform infrared microspectroscopy reveals biochemical changes associated with glioma stem cell differentiation

Kenig

Bedolla

Birarda

et al. 2015

Biophysical Chemistry

View full text Add to dashboard Cite

“…Indeed, the presence of the receptor in the membrane marks a highly aggressive subpopulation of GBMCSCs (27) and EGFR signaling has been linked to the expression of stem cell features in GBMs (28). More recently, it has been demonstrated that EGFR is downregulated upon GBM differentiation and that EGFR signaling blockade leads to decreased tumorigenic and stem cell-like potential of GBM neurospheres (29). Therefore, dacomitinib could be targeting specifically the GBM-CSC population.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma

Zahonero

Aguilera

Ramírez-Castillejo

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Glioblastomas (GBM) are devastating tumors in which there has been little clinical improvement in the last decades. New molecularly directed therapies are under development. EGFR is one of the most promising targets, as this receptor is mutated and/or overexpressed in nearly half of the GBMs. However, the results obtained with first-generation tyrosine-kinase inhibitors have been disappointing with no clear predictive markers of tumor response. Here, we have tested the antitumoral efficacy of a second-generation inhibitor, dacomitinib (PF299804, Pfizer), that binds in an irreversible way to the receptor. Our results confirm that dacomitinib has an effect on cell viability, self-renewal, and proliferation in EGFR-amplified AE EGFRvIII GBM cells. Moreover, systemic administration of dacomitinib strongly impaired the in vivo tumor growth rate of these EGFR-amplified cell lines, with a decrease in the expression of stem cell-related markers. However, continuous administration of the compound was required to maintain the antitumor effect. The data presented here confirm that dacomitinib clearly affects receptor signaling in vivo and that its strong antitumoral effect is independent of the presence of mutant receptor isoforms although it could be affected by the PTEN status (as it is less effective in a PTEN-deleted GBM line). Dacomitinib is being tested in second line for EGFR-amplified GBMs. We hope that our results could help to select retrospectively molecular determinants of this response and to implement future trials with dacomitinib (alone or in combination with other inhibitors) in newly diagnosed GBMs. Mol Cancer Ther; 14(7); 1548-58. Ó2015 AACR.

show abstract

“…However, the CD8 ϩ depletion study could not discriminate between virus replication following ablation of cell-mediated immune control and massive homeostatic proliferation of virus strains from the reservoir that are unable to complete full cycles of replication due to the massive immune activation of the CD4 ϩ T cells induced by the CD8 ϩ cell-depleting antibody (24). However, the latter scenario is unlikely, as the levels of viral replication following CD8 ϩ cell depletion were Ͼ10 4 vRNA copies/ml (14), higher than those characteristic of homeostatic proliferation of CD4 ϩ cells (25)(26)(27). Due to the sample limitation that precluded application of conventional virus outgrowth assay to assess the replicative potential of the rebounding virus and the fact that this method has limitations in identifying the inducible virus (28), we opted for an in vivo assessment of the replication competence of SIVsab in latently infected RMs.…”

mentioning

confidence: 88%

Simian Immunodeficiency Virus SIVsab Infection of Rhesus Macaques as a Model of Complete Immunological Suppression with Persistent Reservoirs of Replication-Competent Virus: Implications for Cure Research

Cillo

et al. 2015

J Virol

View full text Add to dashboard Cite

Simian immunodeficiency virus SIVsab infection is completely controlled in rhesus macaques (RMs) through functional immune responses. We report that in SIVsab-infected RMs, (i) viral replication is controlled to <0 to 3 copies/ml, (ii) about onethird of the virus strains in reservoirs are replication incompetent, and (iii) rebounding virus after CD8؉ cell depletion is replication competent and genetically similar to the original virus stock, suggesting early reservoir seeding. This model permits assessment of strategies aimed at depleting the reservoir without multidrug antiretroviral therapy. The report of one patient that was cured of human immunodeficiency virus (HIV) infection (1) renewed enthusiasm for cure research aimed at understanding the mechanisms of HIV persistence and developing therapeutic strategies to reduce/eliminate viral reservoirs (2). However, virus rebound in the Mississippi baby (3) and the Boston patients (4) pointed to the difficulty of achieving a cure/functional cure of HIV infection and the need to develop new strategies to reach this goal. Multiple limitations to the cure have been identified, including (i) rapid establishment of latently infected cells, (ii) residual viral replication in patients receiving combination antiretroviral therapy (cART), which prevents proper reservoir characterization, and (iii) the existence of anatomic reservoirs (privileged sites of latency insufficiently penetrated by drugs) (5, 6). Due to these limitations, it is generally agreed that a more feasible alternative to an HIV infection cure (i.e., complete eradication of HIV and HIV-infected cells from the body) may be a functional cure (i.e., control of HIV infection without complete HIV eradication: undetectable viremia without ART, no disease progression, no CD4 ϩ T-cell loss, and lack of HIV transmission) (6). This concept is supported by the observation that functional cure has been achieved in a fraction of patients that received long-term ART initiated during acute HIV infection (7).Aside from the general barriers to a cure, there are specific limitations to cure research: (i) ethical problems (therapy cannot be stopped in patients without the risks of virus rebound and the development of viral resistance and increased virus transmission), (ii) technical problems (there is no acceptable biomarker for latently infected cells), and (iii) limited availability of invasive samples from the multiple potential reservoir sites (8). These limitations make it imperative that cure research be performed in analogous and tractable animal models. Currently available models need to be improved for such studies. For example, SIVmac infection of rhesus macaques (RMs) (the most widely used animal model for AIDS research) is more difficult to control with ART than HIV-1 infection in humans, requiring complex combination therapies (9, 10). Furthermore, infection with molecular clones (e.g., simian-human immunodeficiency viruses carrying the reverse transcriptase gene [RT-SHIVs]) does not permit tracking of viral spr...

show abstract

Differentiation of glioblastoma multiforme stem-like cells leads to downregulation of EGFR and EGFRvIII and decreased tumorigenic and stem-like cell potential

Cited by 33 publications

References 42 publications

Fourier transform infrared microspectroscopy reveals biochemical changes associated with glioma stem cell differentiation

Fourier transform infrared microspectroscopy reveals biochemical changes associated with glioma stem cell differentiation

Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma

Simian Immunodeficiency Virus SIVsab Infection of Rhesus Macaques as a Model of Complete Immunological Suppression with Persistent Reservoirs of Replication-Competent Virus: Implications for Cure Research

Contact Info

Product

Resources

About