Molecular Predictors in Glioblastoma

Colman, Howard; Aldape, Ken

doi:10.1001/archneur.65.7.877

Cited by 63 publications

(46 citation statements)

References 47 publications

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“…32 CD15 was also convincingly shown in numerous GSCs to be a tumor-initiating marker 33 and other studies have shown a wide variety of markers (such as L1CAM, 11 and integrin a6…”

Section: Gsc Subtype-specific Markers In Tumorsmentioning

confidence: 82%

“…15 Similarly, a set of genes has been shown to reliably predict the outcome of GBM patients and can potentially guide patients to investigate alternative, more exploratory therapeutic options for tumors that are refractory to current therapies. 11 Bhat et al 5 presented experimental data showing that the conventional antibiotic agent, minocycline, may represent one such candidate treatment for patients with GBM with the MES signature. This agent is clinically attractive because it is already approved by the FDA and has well-known pharmacokinetics and toxicity profiles, 27 is off patent (which would minimize costs), and is known to cross the blood-brain barrier.…”

Section: Clinical Significancementioning

confidence: 99%

“…Aside from this open question, a recent systems biology approach effectively inferred the master regulators that choreograph MES transformation of glioma. 6,9,11 For example, C/EBPb and STAT3 are the two major master regulators necessary in HGG cells for MES transformation. MES transformation results from the concurrent activation of these two conflicting transcriptional regulators normally operating to drive opposing signals (neurogenesis by C/EBPb vs gliogenesis by STAT3).…”

Section: Distinct Oncogene Pathways Regulating Stem Cell Signatures Imentioning

confidence: 99%

“…We found that ALDH1A9 and ALDH1A3, the enzymes that catalyze conversion of acetaldehyde into acetate, are markedly increased in MES GSCs. Detection of HGG by 11 C-acetate PET based on increased activity of these two enzymes has recently been reported. 36 Thus, potential clinical application of 11 C-acetate PET would also be useful for evaluation of subtypes of human HGGs as well as differential diagnosis of tumor recurrence versus radiation necrosis.…”

mentioning

confidence: 99%

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Stem cell signature in glioblastoma: therapeutic development for a moving target

Nakano¹

2015

JNS

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A hAllmArk of high-grade gliomas (HGGs), including the most malignant grade, glioblastoma (GBM), is their resistance to current therapies, which leads to extremely poor prognosis. Even patients with well-demarcated tumors in noneloquent areas that allow maximal gross-total resection at surgery and respond well to irradiation and the first-round chemotherapies inevitably develop tumor regrowth/recurrence resulting in a dismal outcome. Therefore, a better understanding of the molecular mechanisms of such malignancy is warranted in order that we may eventually provide novel and effective therapies for patients.Accumulated evidence has suggested that multiple genetic and metabolic pathways create intricate signaling networks to facilitate crosstalk between oncogenic and onco-metabolic pathways that contribute to cancer initiation and propagation and to therapy resistance. Recent genome-wide expression profiling and global DNA methylation analysis followed by clinical assessment have clearly separated HGGs into 3 distinct subtypes: proneural (PN), mesenchymal (MES), and classical (or proliferative) ( Table 1). 29,34,37 Among these 3 subtypes, approximately half of HGGs with the PN signature are associated with CpG island methylator phenotype (CIMP + ), mutations in the metabolic enzyme IDH1, and the onco-metabolite 2-hydroxyglutarate. 24 Clinically, this group of HGGs, which tend to slowly progress from low-grade glioma to eventual GBM, was previously classified as secondary GBM. From the therapeutic standpoint, treatment plans for this subclass should be designed separately, given the significantly better prognosis compared with the rest of the HGG tumor subtypes. The remaining half of PN tumors are associated with PDGFFRa overexpression and/or amplification. 7,34,37 Although these two PN subtypes show overlapping gene signatures, the therapeutic response and patient outcome appear to be distinct (for undetermined reasons). In contrast, MES tumors are non-CIMP, retain wild-type IDH1, and are associated with somatic mutations and/or deregulated expression in the NF1 gene and its associated pathway. In contrast to this sharp difference in the altered KeY wOrDS cancer stem cells; GBM; brain tumor; tumor heterogeneity; clonal evolution; mesenchymal; oncology aBBreviatiONS ALDH = aldehyde dehydrogenase; CIMP = CpG island methylator phenotype; CSC = cancer stem cell; EMT = epithelial-mesenchymal transition; GBM = glioblastoma; GSC = glioma stem cell; HGG = high-grade glioma; MES = mesenchymal; NSC = neural stem cell; PN = proneural.

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“…32 CD15 was also convincingly shown in numerous GSCs to be a tumor-initiating marker 33 and other studies have shown a wide variety of markers (such as L1CAM, 11 and integrin a6…”

Section: Gsc Subtype-specific Markers In Tumorsmentioning

confidence: 82%

Section: Clinical Significancementioning

confidence: 99%

Section: Distinct Oncogene Pathways Regulating Stem Cell Signatures Imentioning

confidence: 99%

mentioning

confidence: 99%

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Stem cell signature in glioblastoma: therapeutic development for a moving target

Nakano¹

2015

JNS

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“…This seems to be of particular importance in GBM, as these tumors have evolved alternating mechanisms of treatment resistance so that a monotherapy might not target the whole tumor cell population (Cavaliere et al, 2007). To design new, successful strategies, a precise knowledge of tumor-specific alterations is needed, and one promising target for such an approach in GBM is the PI3K/Akt pathway (Colman and Aldape, 2008;Maira et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair

et al. 2009

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Glioblastoma cancer stem cells: heterogeneity, microenvironment and related therapeutic strategies

Denysenko

Gennero

Roos

et al. 2010

Cell Biochemistry & Function

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Glioblastoma Multiforme (GBM) is an incurable malignancy. GBM patients have a short life expectancy despite aggressive therapeutic approaches based on surgical resection followed by adjuvant radiotherapy and concomitant chemotherapy. Glioblastoma growth is characterized by a high motility of tumour cells, their resistance to both chemo/radio-therapy, apoptosis inhibition leading to failure of conventional therapy. Cancer Stem Cells (CSCs), identified in GBM as well as in many other cancer types, express the membrane antigen prominin-1 (namely CD133). These cells and normal Neural Stem Cells (NSC) share surface markers and properties, i.e. are able to self-renew and differentiate into multiple cell types. Stem cell self-renewal depends on microenvironmental cues, including Extracellular Matrix (ECM) composition and cell types. Therefore, the role of microenvironment needs to be evaluated to clarify its importance in tumour initiation and progression through CSCs. The specific microenvironment of CSCs was found to mimic in part the vascular niche of normal stem cells. The targeting of GMB CSCs may represent a powerful treatment approach. Lastly, in GBM patients cancer-initiating cells contribute to the profound immune suppression that in turn correlated with CSCs STAT3 (CD133 + ). Further studies of microenvironment are needed to better understand the origin of GMB/GBM CSCs and its immunosuppressive properties.

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Molecular Predictors in Glioblastoma

Cited by 63 publications

References 47 publications

Stem cell signature in glioblastoma: therapeutic development for a moving target

Stem cell signature in glioblastoma: therapeutic development for a moving target

The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair

Glioblastoma cancer stem cells: heterogeneity, microenvironment and related therapeutic strategies

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