PI3K Pathway Activation Provides a Novel Therapeutic Target for Pediatric Ependymoma and Is an Independent Marker of Progression-Free Survival

Abstract

Purpose: Currently, there are few effective adjuvant therapies for pediatric ependymoma outside confocal radiation, and prognosis remains poor. The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly activated pathways in cancer. PI3Ks transduce signals from growth factors and cytokines, resulting in the phosphorylation and activation of AKT, which in turn induces changes in cell growth, proliferation, and apoptosis.Experimental Design: PI3K pathway status was analyzed in ependymoma using gene expression data and immunohistochemical analysis of phosphorylated AKT (P-AKT). The effect of the PI3K pathway on cell proliferation was investigated by immunohistochemical analysis of cyclin D1 and Ki67, plus in vitro functional analysis. To identify a potential mechanism of PI3K pathway activation, PTEN protein expression and the mutation status of PI3K catalytic subunit a-isoform gene (PIK3CA) was investigated.Results: Genes in the pathway displayed significantly higher expression in supratentorial than in posterior fossa and spinal ependymomas. P-AKT protein expression, indicating pathway activation, was seen in 72% of tumors (n ¼ 169) and P-AKT expression was found to be an independent marker of a poorer progression-free survival. A significant association between PI3K pathway activation and cell proliferation was identified, suggesting that pathway activation was influencing this process. PTEN protein loss was not associated with P-AKT staining and no mutations were identified in PIK3CA.Conclusions: Our results suggest that the PI3K pathway could act as a biomarker, not only identifying patients with a worse prognosis but also those that could be treated with therapies targeted against the pathway, a strategy potentially effective in a high percentage of ependymoma patients.

Pediatric Ependymoma: A Proteomics Perspective

“…PI3Ks are lipid kinases that transduce signals from growth factors and cytokines influencing diverse biological functions, including cellular proliferation, survival, and motility. The PI3K pathway has been reported to be activated in a large number of ependymoma cases examined by polymerase chain reaction and immunohistochemical analyses (41). It is of great importance that the nanoLC-MS/MS method developed in the present study allows for definite identification of key molecules of the specific pathway, thus allowing for further confirmation (in a quantitative manner) of deregulation of the specific molecules once compared to tissues that are non-malignant (manuscript in preparation).…”

The genetic basis of intradural spinal tumors and its impact on clinical treatment

“…91 Although both PKB and PI3K are potential therapeutic targets, their expression was lower in spinal ependymomas, which could potentially limit their usefulness in treatments of these tumors. Upregulated expression of epidermal growth factor receptor (EGFR) in intracranial ependymomas correlates with poor prognosis; this association was further demonstrated by targeted inhibition of EGFR with gefitinib and with AEE788, which reduced tumor proliferation in an in vivo model.…”

Estudo das alterações na expressão gênica dos ependimomas

“…Esses genes já foram descritos em outras casuísticas de ependimomas com IGF2 relacionado aos tumores de localização intracraniana (Korshunov, Neben et al 2003;Modena, Lualdi et al 2006), membros da família FGFR às lesões anaplásicas (Korshunov, Neben et al 2003), a via Notch (NOTCH1 e seus ligantes) às lesões intracranianas, supratentoriais (Taylor, Poppleton et al 2005;Modena, Lualdi et al 2006;Palm, FigarellaBranger et al 2009;Johnson, Wright et al 2010) e CCND1 ora relacionado às lesões supratentoriais (Taylor, Poppleton et al 2005;Rogers, Mayne et al 2013), ora às lesões anaplásicas (Prayson 1998;Korshunov, Neben et al 2003;Palm, Figarella-Branger et al 2009), ora à população pediátrica (Modena, Lualdi et al 2006). O gene IGF2 codifica uma proteína com função hormonal (Bergman, Halje et al 2013).…”

“…Há descrição desse marcador como fator prognóstico em outros cânceres, conforme discutido acima, porém com definição pouco precisa da sua importância nos ependimomas. Maiores níveis de expressão de ciclina D1 foram observados nas amostras de tumor de localização supratentorial e nas lesões anaplásicas, confirmando a análise da expressão gênica e conforme descrição por outros autores (Prayson 1998;Korshunov, Neben et al 2003;Taylor, Poppleton et al 2005;Palm, Figarella-Branger et al 2009;Rogers, Mayne et al 2013). As amostras de tumores de pacientes da população pediátrica também apresentaram maiores níveis de expressão de ciclina D1 em comparação às amostras de pacientes adultos, relação não observada durante a análise da expressão gênica, porém já observada por outro autor (Modena, Lualdi et al 2006).…”

“…Análise recente da ativação da via PI3K nos ependimomas descreveu maior expressão de ciclina D1 em tumores de localização supratentorial (Rogers, Mayne et al 2013;Parker, Mohankumar et al 2014). Há interações da via Notch, IGF1R e via FGF com o sistema PI3K/AKT, sistema esse que tem um papel crítico na proliferação, progressão do ciclo celular e apoptose em alguns cânceres humanos (Shin, Minter et al 2006;Palomero, Dominguez et al 2008;Guo, Ye et al 2009;Liu, Cheng et al 2009;Hales, Taub et al 2014).…”