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166


CHARACTERIZATION OF GPR133 EXPRESSION IN GLIOMA SUBTYPES [Meeting Abstract]

Kader, Michael; Frenster, Joshua; Liechty, Benjamin; Modrek, Aram; Tsirigos, Aristotelis; Golfinos, John; Eisele, Sylvia; Jain, Rajan; Shepherd, Timothy; Fatterpekar, Girish; MacNeil, Douglas; Shohdy, Nadim; Huang, Xinyan; Chi, Andrew S; Snuderl, Matija; Zagzag, David; Placantonakis, Dimitris
ISI:000415152500139
ISSN: 1523-5866
CID: 2802482

A PHASE II, OPEN-LABEL, SINGLE ARM, MULTICENTER STUDY OF AVELUMAB WITH HYPOFRACTIONATED RE-IRRADIATION IN ADULT SUBJECTS WITH TRANSFORMED IDH MUTANT GLIOBLASTOMA [Meeting Abstract]

Chi, Andrew S; Eisele, Sylvia; Arrillaga-Romany, Isabel; Batchelor, Tracy; Cahill, Daniel; Taylor, Jennie; Cloughesy, Timothy F; Patel, Amie; Delara, Malcolm; Latchman, Sunita; Placantonakis, Dimitris; Pacione, Donato; Fatterpekar, Girish; Shepherd, Timothy; Jain, Rajan; Cordova, Christine; Schafrick, Jessica; Snuderl, Matija; Zagzag, David; Kondziolka, Douglas; Golfinos, John; Silverman, Joshua
ISI:000415152500099
ISSN: 1523-5866
CID: 2802502

PATH-42. DETECTION OF TERT MUTATIONS IN CELL-FREE CIRCULATING TUMOR DNA (ctDNA) OF GLIOBLASTOMA PATIENTS USING DROPLET DIGITAL PCR

Cordova, Christine; Corless, Broderick; Syeda, Mahrukh; Patel, Amie; Delara, Malcolm; Eisele, Sylvia; Schafrick, Jessica; Placantonakis, Dimitris; Pacione, Donato, Silverman, Joshua; Fatterpekar, Girish; Shepherd, Timothy; Jain, Rajan; Snuderl, Matja; Zagzag, David; Golfinos, John; Jafar, Jafar J; Shao, Yongzhao; Karlin-Neumann, George; Polsky, David; Chi, Andrew S
ORIGINAL:0014233
ISSN: 1523-5866
CID: 4033762

Low-Grade Astrocytoma Mutations in IDH1, P53, and ATRX Cooperate to Block Differentiation of Human Neural Stem Cells via Repression of SOX2

Modrek, Aram S; Golub, Danielle; Khan, Themasap; Bready, Devin; Prado, Jod; Bowman, Christopher; Deng, Jingjing; Zhang, Guoan; Rocha, Pedro P; Raviram, Ramya; Lazaris, Charalampos; Stafford, James M; LeRoy, Gary; Kader, Michael; Dhaliwal, Joravar; Bayin, N Sumru; Frenster, Joshua D; Serrano, Jonathan; Chiriboga, Luis; Baitalmal, Rabaa; Nanjangud, Gouri; Chi, Andrew S; Golfinos, John G; Wang, Jing; Karajannis, Matthias A; Bonneau, Richard A; Reinberg, Danny; Tsirigos, Aristotelis; Zagzag, David; Snuderl, Matija; Skok, Jane A; Neubert, Thomas A; Placantonakis, Dimitris G
Low-grade astrocytomas (LGAs) carry neomorphic mutations in isocitrate dehydrogenase (IDH) concurrently with P53 and ATRX loss. To model LGA formation, we introduced R132H IDH1, P53 shRNA, and ATRX shRNA into human neural stem cells (NSCs). These oncogenic hits blocked NSC differentiation, increased invasiveness in vivo, and led to a DNA methylation and transcriptional profile resembling IDH1 mutant human LGAs. The differentiation block was caused by transcriptional silencing of the transcription factor SOX2 secondary to disassociation of its promoter from a putative enhancer. This occurred because of reduced binding of the chromatin organizer CTCF to its DNA motifs and disrupted chromatin looping. Our human model of IDH mutant LGA formation implicates impaired NSC differentiation because of repression of SOX2 as an early driver of gliomagenesis.
PMCID:5687844
PMID: 29091765
ISSN: 2211-1247
CID: 2758982

Resection of a Pediatric Thalamic Juvenile Pilocytic Astrocytoma with Whole Brain Tractography

Weiner, Howard L; Placantonakis, Dimitris G
The resection of deep-seated brain tumors has been associated with morbidity due to injury to critical neural structures during the approach. Recent technological advancements in navigation and stereotaxy, surgical planning, brain tractography and minimal-access brain ports present the opportunity to overcome such limitations. Here, we present the case of a pediatric patient with a left thalamic/midbrain juvenile pilocytic astrocytoma (JPA). The tumor displaced the corticospinal fibers posteriorly and resulted in hemiparesis. Using whole brain tractography to plan a corridor for the approach, neuronavigation, a tubular retractor and an exoscope for visualization, we obtained gross total resection of the tumor, while minimizing injury to white matter bundles, including the corticospinal fibers. We propose that surgical planning with whole brain tractography is essential for reducing morbidity while accessing deep-lying brain lesions via retractor tubes, by means of sparing critical fiber tracts.
PMCID:5724810
PMID: 29234572
ISSN: 2168-8184
CID: 2844332

GPR133 Promotes Glioblastoma Growth in Hypoxia

Frenster, Joshua D; Inocencio, Julio F; Xu, Zhongye; Dhaliwal, Joravar; Alghamdi, Abdulhakeem; Zagzag, David; Bayin, N Sumru; Placantonakis, Dimitris G
PMID: 28899043
ISSN: 1524-4040
CID: 2701492

Using Nanoflow LC-MS/MS to Study Metabolic Changes in Low Grade Astrocytoma [Meeting Abstract]

Neubert, Thomas A; Modrek, Aram; Deng, Jingjing; Zhang, Guoan; Placantonakis, Dimitris
ISI:000407623600096
ISSN: 1535-9484
CID: 2676972

Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons

Pourchet, Aldo; Modrek, Aram S; Placantonakis, Dimitris G; Mohr, Ian; Wilson, Angus C
Herpes simplex virus 1 (HSV-1) uses latency in peripheral ganglia to persist in its human host, however, recurrent reactivation from this reservoir can cause debilitating and potentially life-threatening disease. Most studies of latency use live-animal infection models, but these are complex, multilayered systems and can be difficult to manipulate. Infection of cultured primary neurons provides a powerful alternative, yielding important insights into host signaling pathways controlling latency. However, small animal models do not recapitulate all aspects of HSV-1 infection in humans and are limited in terms of the available molecular tools. To address this, we have developed a latency model based on human neurons differentiated in culture from an NIH-approved embryonic stem cell line. The resulting neurons are highly permissive for replication of wild-type HSV-1, but establish a non-productive infection state resembling latency when infected at low viral doses in the presence of the antivirals acyclovir and interferon-alpha. In this state, viral replication and expression of a late viral gene marker are not detected but there is an accumulation of the viral latency-associated transcript (LAT) RNA. After a six-day establishment period, antivirals can be removed and the infected cultures maintained for several weeks. Subsequent treatment with sodium butyrate induces reactivation and production of new infectious virus. Human neurons derived from stem cells provide the appropriate species context to study this exclusively human virus with the potential for more extensive manipulation of the progenitors and access to a wide range of preexisting molecular tools.
PMCID:5488658
PMID: 28594343
ISSN: 2076-0817
CID: 2590522

LOW-GRADE ASTROCYTOMA CORE MUTATIONS IN IDH1, P53 AND ATRX COOPERATE TO BLOCK DIFFERENTIATION OF HUMAN NEURAL STEM CELLS VIA EPIGENETIC REPRESSION OF SOX2 [Meeting Abstract]

Modrek, Aram; Golub, Danielle; Khan, Themasap; Prado, Jod; Bowman, Christopher; Deng, Jingjing; Zhang, Guoan; Rocha, Pedro; Raviram, Ramya; Lazaris, Harris; Kader, Michael; Dhaliwal, Joravar; Chi, Andrew; Golfinos, John; Tsirigos, Aristotelis; Zagzag, David; Snuderl, Matija; Skok, Jane; Neubert, Thomas; Placantonakis, Dimitris
ISI:000402766800146
ISSN: 1523-5866
CID: 2591472

Patient-Specific Screening Using High-Grade Glioma Explants to Determine Potential Radiosensitization by a TGF-beta Small Molecule Inhibitor

Bayin, N Sumru; Ma, Lin; Thomas, Cheddhi; Baitalmal, Rabaa; Sure, Akhila; Fansiwala, Kush; Bustoros, Mark; Golfinos, John G; Pacione, Donato; Snuderl, Matija; Zagzag, David; Barcellos-Hoff, Mary Helen; Placantonakis, Dimitris
High-grade glioma (HGG), a deadly primary brain malignancy, manifests radioresistance mediated by cell-intrinsic and microenvironmental mechanisms. High levels of the cytokine transforming growth factor-beta (TGF-beta) in HGG promote radioresistance by enforcing an effective DNA damage response and supporting glioma stem cell self-renewal. Our analysis of HGG TCGA data and immunohistochemical staining of phosphorylated Smad2, which is the main transducer of canonical TGF-beta signaling, indicated variable levels of TGF-beta pathway activation across HGG tumors. These data suggest that evaluating the putative benefit of inhibiting TGF-beta during radiotherapy requires personalized screening. Thus, we used explant cultures of seven HGG specimens as a rapid, patient-specific ex vivo platform to test the hypothesis that LY364947, a small molecule inhibitor of the TGF-beta type I receptor, acts as a radiosensitizer in HGG. Immunofluorescence detection and image analysis of gamma-H2AX foci, a marker of cellular recognition of radiation-induced DNA damage, and Sox2, a stem cell marker that increases post-radiation, indicated that LY364947 blocked these radiation responses in five of seven specimens. Collectively, our findings suggest that TGF-beta signaling increases radioresistance in most, but not all, HGGs. We propose that short-term culture of HGG explants provides a flexible and rapid platform for screening context-dependent efficacy of radiosensitizing agents in patient-specific fashion. This time- and cost-effective approach could be used to personalize treatment plans in HGG patients.
PMCID:5156509
PMID: 27978994
ISSN: 1476-5586
CID: 2363642