Transcriptional diversity of long-term glioblastoma survivors

Gerber, Naamit K.; Goenka, Anuj; Turcan, Şevin; Reyngold, Marsha; Makarov, Vladimir; Kannan, Kasthuri; Beal, Kathryn; Omuro, Antonio; Yamada, Yoshiya; Gutin, Phillip H.; Brennan, Cameron; Huse, Jason T.; Chan, Timothy A.

doi:10.1093/neuonc/nou043

Cited by 78 publications

(67 citation statements)

References 25 publications

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“…Recently, a pro-tumorigenic inflammation signature has been described for IDH wt STS [16]. In addition to confirming this finding, we have resolved these expression differences further.…”

Section: Discussionsupporting

confidence: 79%

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Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain

et al. 2015

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Glioblastoma (GBM) is a devastating tumor and few patients survive beyond 3 years. Defining the molecular determinants underlying long-term survival is essential for insights into tumor biology and biomarker identification. We therefore investigated homogeneously treated, IDH (wt) long-term (LTS, n = 10) and short-term survivors (STS, n = 6) by microarray transcription profiling. While there was no association of clinical parameters and molecular subtypes with long-term survival, STS tumors were characterized by differential polarization of infiltrating microglia with predominance of the M2 phenotype detectable both on the mRNA and protein level. Furthermore, transcriptional signatures of LTS and STS predicted patient outcome in a large, IDH (wt) cohort (n = 468). Interrogation of overlapping genomic alterations identified concurrent gain of chromosomes 19 and 20 as a favorable prognostic marker. The strong association of this co-gain with survival was validated by aCGH in a second, independent cohort (n = 124). Finally, FISH and gene expression data revealed gains to constitute low-amplitude, clonal events with a strong impact on transcription. In conclusion, these findings provide important insights into the manipulation of the innate immune system by particularly aggressive GBM tumors. Furthermore, we genomically characterize a previously unknown, clinically relevant subgroup of glioblastoma, which can easily be identified through modern neuropathological workup.

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“…Recently, a pro-tumorigenic inflammation signature has been described for IDH wt STS [16]. In addition to confirming this finding, we have resolved these expression differences further.…”

Section: Discussionsupporting

confidence: 79%

“…A number of recent publications on the transcriptome of GBM LTS have assessed mesenchymal, proneural, classical and neural subtypes among their patient cohorts [16,46]. However, none of these studies validated differences in gene expression between LTS and STS in a larger number of tumors.…”

Section: Lts and Sts Expression Profiles Are Prognostic In Non-g-cimpmentioning

confidence: 99%

Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain

et al. 2015

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“…Interesting links in glioma to MDA-9/Syntenin-related signaling have emerged recently. Database expression profiles comparing long-term survivors (LTSs) of GBM (>48 mo) with short-term survivors (<12 mo) revealed a 40% decrease in IGFBP-2, a noted downstream product of MDA-9/Syntenin signaling (9), in LTS tumors (31). Additionally, identification of a radiosensitive gene signature via expression data from the NCI-60 cancer cell panel revealed that a recognized MDA-9/Syntenin binding partner, integrin-linked kinase (32), was significantly down-regulated in radiosensitive cells (33).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

Kegelman

Das

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

130

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Glioblastoma multiforme (GBM) is an intractable tumor despite therapeutic advances, principally because of its invasive properties. Radiation is a staple in therapeutic regimens, although cells surviving radiation can become more aggressive and invasive. Subtraction hybridization identified melanoma differentiation-associated gene 9 [MDA-9/Syntenin; syndecan-binding protein (SDCBP)] as a differentially regulated gene associated with aggressive cancer phenotypes in melanoma. MDA-9/Syntenin, a highly conserved double-PDZ domain-containing scaffolding protein, is robustly expressed in human-derived GBM cell lines and patient samples, with expression increasing with tumor grade and correlating with shorter survival times and poorer response to radiotherapy. Knockdown of MDA-9/Syntenin sensitizes GBM cells to radiation, reducing postradiation invasion gains. Radiation induces Src and EGFRvIII signaling, which is abrogated through MDA-9/Syntenin down-regulation. A specific inhibitor of MDA-9/Syntenin activity, PDZ1i (113B7), identified through NMR-guided fragment-based drug design, inhibited MDA-9/Syntenin binding to EGFRvIII, which increased following radiation. Both genetic (shmda-9) and pharmacological (PDZ1i) targeting of MDA-9/Syntenin reduced invasion gains in GBM cells following radiation. Although not affecting normal astrocyte survival when combined with radiation, PDZ1i radiosensitized GBM cells. PDZ1i inhibited crucial GBM signaling involving FAK and mutant EGFR, EGFRvIII, and abrogated gains in secreted proteases, MMP-2 and MMP-9, following radiation. In an in vivo glioma model, PDZ1i resulted in smaller, less invasive tumors and enhanced survival. When combined with radiation, survival gains exceeded radiotherapy alone. MDA-9/Syntenin (SDCBP) provides a direct target for therapy of aggressive cancers such as GBM, and defined small-molecule inhibitors such as PDZ1i hold promise to advance targeted brain cancer therapy.

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“…We expect that the next several years will produce multiple prospective trials to investigate novel combination therapies beyond anti-angiogenic therapies and dose escalation. The integration of rationally selected targeted agents after gaining an improved understanding of the genomic landscape of GBM will be critical to significantly improve outcomes[68]. …”

Section: Five-year Viewmentioning

confidence: 99%

External beam re-irradiation, combination chemoradiotherapy, and particle therapy for the treatment of recurrent glioblastoma

Taunk

Moraes

Escorcia

et al. 2016

Expert Review of Anticancer Therapy

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SUMMARYGlioblastoma is a common aggressive primary malignant brain tumor, and is nearly universal in progression and mortality after initial treatment. Re-irradiation presents a promising treatment option for progressive disease, both palliating symptoms and potentially extending survival. Highly conformal radiation techniques such as stereotactic radiosurgery and hypofractionated radiosurgery are effective short courses of treatment that allow delivery of high doses of therapeutic radiation with steep dose gradients to protect normal tissue. Patients with higher performance status, younger age, and longer interval between primary treatment and progression represent the best candidates for re-irradiation. Multiple studies are also underway involving combinations of radiation and systemic therapy to bend the survival curve and improve the therapeutic index. In the multimodal treatment of recurrent high-grade glioma, the use of surgery, radiation, and systemic therapy should be highly individualized. Here we comprehensively review radiation therapy and techniques, along with discussion of combination treatment and novel strategies.

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Transcriptional diversity of long-term glioblastoma survivors

Cited by 78 publications

References 25 publications

Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain

Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain

Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

External beam re-irradiation, combination chemoradiotherapy, and particle therapy for the treatment of recurrent glioblastoma

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