Molecular and cellular heterogeneity: the hallmark of glioblastoma

Aum, Diane J.; Kim, David H.; Beaumont, Thomas L.; Leuthardt, Eric C.; Dunn, Gavin P.; Kim, Albert H.

doi:10.3171/2014.9.focus14521

Cited by 167 publications

(117 citation statements)

References 70 publications

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“…Because glioblastomas are heterogeneous (26), we examined the subclonal architecture of the primary brain tumor and the two spinal metastases to determine how it changed over the course of 2 different treatments. Clonal analysis revealed 4 distinct mutation clusters in the treatment naïve brain tumor, of which one was the founder clone (Figure 2A–C, Supplemental Table 6).…”

Section: Resultsmentioning

confidence: 99%

Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy

et al. 2016

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We present the case of a patient with a left frontal glioblastoma with PNET features and hypermutated genotype in the setting of a POLE germline alteration. During standard-of-care chemoradiation, the patient developed a cervical spine metastasis and was subsequently treated with Pembrolizumab. Shortly thereafter, the patient developed an additional metastatic spinal lesion. Using whole exome DNA sequencing and clonal analysis, we report changes in the subclonal architecture throughout treatment. Furthermore, a persistently high neoantigen load was observed within all tumors. Interestingly, following initiation of Pembrolizumab, brisk lymphocyte infiltration was observed in the subsequently resected metastatic spinal lesion and an objective radiographic response was noted in a progressive intracranial lesion suggestive of active CNS immunosurveillance following checkpoint blockade therapy.

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Section: Resultsmentioning

confidence: 99%

Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy

et al. 2016

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“…GBM has a peak incidence in adults older than 40 years of age, with 2.96 cases per 100,000 people per annum in the USA (Ostrom et al, 2015). Local invasiveness, neoangiogenesis, and intratumor heterogeneity are among the most important hallmarks of the aggressiveness of GBM (Jain et al, 2007; Aum et al, 2014; Paw et al, 2015). Conventional GBMs can be subdivided into primary and secondary tumors on the basis of clinicopathologic stratification (Kleihues and Ohgaki, 1999).…”

Section: Introductionmentioning

confidence: 99%

Glioblastoma Stem-Like Cells: Characteristics, Microenvironment, and Therapy

et al. 2016

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Glioblastoma multiforme (GBM), grade IV astrocytoma, is the most fatal malignant primary brain tumor. GBM contains functional subsets of cells called glioblastoma stem-like cells (GSCs), which are radioresistant and chemoresistant and eventually lead to tumor recurrence. Recent studies showed that GSCs reside in particular tumor niches that are necessary to support their behavior. To successfully eradicate GBM growth and recurrence, new strategies selectively targeting GSCs and/or their microenvironmental niche should be designed. In this regard, here we focus on elucidating the molecular mechanisms that govern these GSC properties and on understanding the mechanism of the microenvironmental signals within the tumor mass. Moreover, to overcome the blood–brain barrier, which represents a critical limitation of GBM treatments, a new drug delivery system should be developed. Nanoparticles can be easily modified by different methods to facilitate delivery efficiency of chemotherapeutics, to enhance the accumulation within the tumors, and to promote the capacity for targeting the GSCs. Therefore, nanotechnology has become the most promising approach to GSC-targeting therapy. Additionally, we discussed the future of nanotechnology-based targeted therapy and point out the disadvantages that should be overcome.

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“…The initial enthusiasm that extensive genomic profiling of driver mutations, of which GBM was one of the first to be characterized by The Cancer Genome Atlas (TCGA), 1,2 would lead to effective molecularly targeted therapy for central nervous system (CNS) malignancies has yet to come to fruition. The reason for the failure of this "mutation-to-drug" paradigm is likely multifactorial, including the subclonal heterogeneity of GBM 3 and the necessity of systemically delivered drugs to penetrate the bloodbrain barrier(BBB) at a sufficient concentration to be efficacious. As such, any new treatment approach will need to address these complexities of GBM if it is to be successful.…”

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confidence: 99%