An Integrated In Vitro and In Vivo High-Throughput Screen Identifies Treatment Leads for Ependymoma

Atkinson, Jennifer M.; Shelat, Anang A.; Carcaboso, Ángel M.; Kranenburg, Tanya A.; Arnold, Leggy A.; Boulos, Nidal; Wright, Karen; Johnson, Robert A.; Poppleton, Helen; Mohankumar, Kumarasamypet M.; Féau, Clémentine; Phoenix, Timothy N.; Gibson, Paul; Zhu, Linghui; Tong, Yiai; Eden, C.G. van; Ellison, David W.; Priebe, Waldemar; Koul, Dimpy; Yung, W.K. Alfred; Gajjar, Amar; Stewart, Clinton F.; Guy, R. Kiplin; Gilbertson, Richard J.

doi:10.1016/j.ccr.2011.08.013

Cited by 108 publications

(116 citation statements)

References 56 publications

Supporting

Mentioning

109

Contrasting

Unclassified

Order By: Relevance

“…In a recent drug screen of a model of a supratentorial subtype of ependymoma, inhibitors of IGF1R, which signals through the PI3K pathway, and GSK3b were found to disrupt cell proliferation, supporting our conclusions (35). A number of drugs have been developed against the PI3K pathway, many of which are undergoing clinical trials, including in adult glioma (22,36).…”

Section: Discussionsupporting

confidence: 78%

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

Rogers

Mayne

Chapman

et al. 2013

Clinical Cancer Research

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 78%

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

Rogers

Mayne

Chapman

et al. 2013

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…For example, kinase-targeting techniques were used to discover that inhibition of heat shock protein 90 may cause destabilization in the MAPK pathway (Haupt et al, 2012). Kinome-wide assays were also used in the discovery of treatment leads for ependymoma, a chemoresistant brain tumor (Atkinson et al, 2011). Finally, targeting of kinase activity in the MET/HGF (hepatocyte growth factor) pathway has led to Phase 3 studies of MET-targeting agents for the treatment of lung cancer (Feng et al, 2012).…”

Section: Measuring Kinase Activity: Kinome Arraysmentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

103

View full text Add to dashboard Cite

We propose that postmortem tissue is an underutilized substrate that may be used to translate genetic and/or preclinical studies, particularly for neuropsychiatric illnesses with complex etiologies. Postmortem brain tissues from subjects with schizophrenia have been extensively studied, and thus serve as a useful vehicle for illustrating the challenges associated with this biological substrate. Schizophrenia is likely caused by a combination of genetic risk and environmental factors that combine to create a disease phenotype that is typically not apparent until late adolescence. The complexity of this illness creates challenges for hypothesis testing aimed at understanding the pathophysiology of the illness, as postmortem brain tissues collected from individuals with schizophrenia reflect neuroplastic changes from a lifetime of severe mental illness, as well as treatment with antipsychotic medications. While there are significant challenges with studying postmortem brain, such as the postmortem interval, it confers a translational element that is difficult to recapitulate in animal models. On the other hand, data derived from animal models typically provide specific mechanistic and behavioral measures that cannot be generated using human subjects. Convergence of these two approaches has led to important insights for understanding molecular deficits and their causes in this illness. In this review, we discuss the problem of schizophrenia, review the common challenges related to postmortem studies, discuss the application of biochemical approaches to this substrate, and present examples of postmortem schizophrenia studies that illustrate the role of the postmortem approach for generating important new leads for understanding the pathophysiology of severe mental illness.

show abstract

“…Application of vorinostat at therapeutically achievable concentrations significantly impaired EP1NS proliferation and self-renewal capacity and induced cell cycle arrest and neuronal differentiation (139). An integrated in vitro and in vivo high-throughput drug screen using another model of ST-EPN, deriving from murine neural stem cells with Cdkn2a deletion and overexpression of Ephb2, demonstrated that the chemotherapeutic agent 5-fluorouracil has selective toxicity against this model (127,140). However, an early clinical study of 5-fluorouracil in a molecularly unselected cohort of children and young adults with recurrent EPN only reported limited response to the drug in these patients (141).…”

Section: Supratentorial Epnmentioning

confidence: 99%

Molecular mechanisms and therapeutic targets in pediatric brain tumors

et al. 2017

View full text Add to dashboard Cite

Brain tumors are among the leading causes of cancer-related deaths in children. Although surgery, aggressive radiation, and chemotherapy have improved outcomes, many patients still die of their disease. Moreover, those who survive often suffer devastating long-term side effects from the therapies. A greater understanding of the molecular underpinnings of these diseases will drive the development of new therapeutic approaches. Advances in genomics and epigenomics have provided unprecedented insight into the molecular diversity of these diseases and, in several cases, have revealed key genes and signaling pathways that drive tumor growth. These not only serve as potential therapeutic targets but also have facilitated the creation of animal models that faithfully recapitulate the human disease for preclinical studies. In this Review, we discuss recent progress in understanding the molecular basis of the three most common malignant pediatric brain tumors-medulloblastoma, ependymoma, and high-grade glioma-and the implications for development of safer and more effective therapies.

show abstract

An Integrated In Vitro and In Vivo High-Throughput Screen Identifies Treatment Leads for Ependymoma

Cited by 108 publications

References 56 publications

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

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

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Molecular mechanisms and therapeutic targets in pediatric brain tumors

Contact Info

Product

Resources

About