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  • 1
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    Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition
    Springer Science and Business Media LLC ; 2017
    In:  Nature Vol. 551, No. 7679 ( 2017-11), p. 247-250
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 551, No. 7679 ( 2017-11), p. 247-250
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/nature24297
    RVK:
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    RVK:
    UA 1000
    RVK:
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
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  • 2
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    Abstract B098: GPX4 is a broadly shared gene vulnerability among residual tumors
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. B098-B098
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. B098-B098
    Abstract: The heterogeneity of tumor cells underlies acquired drug resistance to a variety of therapeutic approaches. The advent of next-generation sequencing has facilitated a wave of studies identifying genetic mutations, which may be preexisting or acquired during treatment, that drive drug resistance and tumor relapse. However, it has recently become clear that non-mutational mechanisms of drug resistance, such as cell state switching from an epithelial to mesenchymal state, can also play an important role in the process of acquired drug resistance. Non-mutational drug resistance is relatively poorly understood and represents fertile ground for the discovery of novel therapeutic targets. Drug-tolerant “persister” cells are an experimental model of non-mutational cancer drug resistance in which small fractions ( & lt;5%) of cells within cancer cell lines survive cytotoxic drug exposure despite lacking resistance-conferring mutations. These residual surviving persister cells occupy a reversible quiescent state with a unique chromatin landscape. Persister cells regrow and become resensitized to drug, reminiscent of clinical observations of secondary responses from retreatment after a drug holiday. Persister cells also eventually obtain genetic mutations and reenter the cell cycle after weeks or months of continuous drug exposure, modeling the process of acquisition of resistance-conferring genetic mutations in patients during treatment. Here, we report on our efforts to identify a widely shared gene vulnerability in persister cells that transcends tissue lineage, genetic mutation background, and drug treatment regimens. Through a functional genomics approach entailing RNA-seq, pathway analysis, and a focused chemical inhibitor screen, we have identified a gene, glutathione peroxidase 4 (GPX4), that is specifically essential to persister cells. When GPX4 is chemically inhibited or genetically ablated, persister cells across a wide range of tissue lineages undergo ferroptosis–a recently discovered mechanism of non-apoptotic caspase-independent cell death. Ferroptosis occurs when lipid peroxides accumulate in cells, and as the only human enzyme capable of scavenging lipid peroxides, GPX4 plays a key role in preventing ferroptosis. Compared to drug-naïve parental cells or nontransformed normal cells, persister cells are strongly differentially sensitive to GPX4 inhibition and ferroptosis. This sensitivity is the result of a disabled antioxidant program in persister cells marked by a global downregulation of antioxidant genes including Nrf2 targets, and decreased levels of reducing cofactors glutathione and NADPH. As a first step toward raising GPX4 as a promising preclinical drug target in vivo, we also show that targeting GPX4 in residual melanoma xenograft tumors prevents tumor relapse. Therefore, GPX4 is an extremely promising drug target that may be exploited to prevent tumor relapse across a wide spectrum of tumor types and drug treatments. Citation Format: Matthew J. Hangauer, Vasanthi S. Viswanathan, Matthew J. Ryan, Dhruv Bole, John K. Eaton, Alexandre Matov, Jacqueline Galeas, Harshil D. Dhruv, Michael E. Berens, Stuart L. Schreiber, Frank McCormick, Michael T. McManus. GPX4 is a broadly shared gene vulnerability among residual tumors [abstract] . In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B098.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-B098
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
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    TROY (TNFRSF19) Promotes Glioblastoma Survival Signaling and Therapeutic Resistance
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Research Vol. 11, No. 8 ( 2013-08-01), p. 865-874
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 11, No. 8 ( 2013-08-01), p. 865-874
    Abstract: Of the features that characterize glioblastoma, arguably none is more clinically relevant than the propensity of malignant glioma cells to aggressively invade into the surrounding normal brain tissue. These invasive cells render complete resection impossible, confer significant resistance to chemo- and radiation-therapy, and virtually assure tumor recurrence. Expression of TROY (TNFRSF19), a member of the TNF receptor superfamily, inversely correlates with patient survival and stimulates glioblastoma cell migration and invasion in vitro. In this study, we report that TROY is overexpressed in glioblastoma tumor specimens and TROY mRNA expression is increased in the invasive cell population in vivo. In addition, inappropriate expression of TROY in mouse astrocytes in vivo using glial-specific gene transfer in transgenic mice induces astrocyte migration within the brain, validating the importance of the TROY signaling cascade in glioblastoma cell migration and invasion. Knockdown of TROY expression in primary glioblastoma xenografts significantly prolonged survival in vivo. Moreover, TROY expression significantly increased resistance of glioblastoma cells to both IR- and TMZ-induced apoptosis via activation of Akt and NF-κB. Inhibition of either Akt or NF-κB activity suppressed the survival benefits of TROY signaling in response to TMZ treatment. These findings position aberrant expression and/or signaling by TROY as a contributor to the dispersion of glioblastoma cells and therapeutic resistance. Implications: Targeting of TROY may increase tumor vulnerability and improve therapeutic response in glioblastoma. Mol Cancer Res; 11(8); 865–74. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-13-0008
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 4
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    SGEF Is Regulated via TWEAK/Fn14/NF-κB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide
    American Association for Cancer Research (AACR) ; 2016
    In:  Molecular Cancer Research Vol. 14, No. 3 ( 2016-03-01), p. 302-312
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 14, No. 3 ( 2016-03-01), p. 302-312
    Abstract: Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors. Despite surgical removal followed by concomitant radiation and chemotherapy with the alkylating agent temozolomide, GB tumors develop treatment resistance and ultimately recur. Impaired response to treatment occurs rapidly, conferring a median survival of just fifteen months. Thus, it is necessary to identify the genetic and signaling mechanisms that promote tumor resistance to develop targeted therapies to combat this refractory disease. Previous observations indicated that SGEF (ARHGEF26), a RhoG-specific guanine nucleotide exchange factor (GEF), is overexpressed in GB tumors and plays a role in promoting TWEAK-Fn14–mediated glioma invasion. Here, further investigation revealed an important role for SGEF in glioma cell survival. SGEF expression is upregulated by TWEAK-Fn14 signaling via NF-κB activity while shRNA-mediated reduction of SGEF expression sensitizes glioma cells to temozolomide-induced apoptosis and suppresses colony formation following temozolomide treatment. Nuclear SGEF is activated following temozolomide exposure and complexes with the DNA damage repair (DDR) protein BRCA1. Moreover, BRCA1 phosphorylation in response to temozolomide treatment is hindered by SGEF knockdown. The role of SGEF in promoting chemotherapeutic resistance highlights a heretofore unappreciated driver, and suggests its candidacy for development of novel targeted therapeutics for temozolomide-refractory, invasive GB cells. Implication: SGEF, as a dual process modulator of cell survival and invasion, represents a novel target for treatment refractory glioblastoma. Mol Cancer Res; 14(3); 302–12. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-15-0183
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 5
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    Abstract 248: Dynamic multi-OMICS analysis of glioblastoma cells reveals context of vulnerability to neddylation inhibition by pevonedistat
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 248-248
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 248-248
    Abstract: As the most lethal primary brain tumor, glioblastoma multiforme (GBM) calls for novel therapeutic development. Global over activation of neddylation (a post-translational modification) has recently been found in GBM patients and has correlated with shorter patient survival. Significant accumulation of neddylation in recurrent GBM tissues indicates its importance in tumorigenesis and tumor progression. Analogous to the ubiquitination pathway, neddylation is essential to many protein regulation and biological processes. Although most well-characterized substrates of neddylation are the cullin subunits of Cullin-RING ligases (CRLs), non-cullin NEDD8 substrates have been investigated in recent years. Neddylation and subsequent degradation of PARC, p53, MDM2 and EGFR exemplify the broader functional role of neddylation. The neddylation inhibitor MLN4924 targets NEDD8 Activating Enzyme (NAE), an upstream activator of neddylation, and, as a result, induces cell cycle arrest, apoptosis and senescence in cancer cells. In this work, we investigated the context of vulnerability to Pevonedistat (MLN4924) in GBM by comparing the dynamic response of sensitive and non-sensitive cells using transcriptomics and proteomics profiling, using long-established and patient derived glioma cell lines. Efficacy of MLN4924 in glioma cell models was evaluated by measuring cell viability (CellTiterGlo®), colony formation efficiency, and cell cycle progression (flow cytometry with propidium iodide staining). GB1 (IC50= 0.28 μM), LN18 (IC50 = 0.19 μM), and GBM43 (IC50= 0.45 μM) were established as sensitive and M059K (IC50= 5.5 μM), SNU1105 (IC50 = 20.9 μM), and GBM39 (IC50= 10.3 μM) as non-sensitive cell lines based on IC50 values. Western blot analysis of known cell cycle regulatory pathways and DNA damage response pathway did not show significant dynamic differences between sensitive and non-sensitive glioma cell models. To discover genomic and/or proteomic markers of differential response we collected RNA and protein for LN18 (sensitive) and SNU1105 (Non-sensitive) cells after 0, 2, 8 and 24 h treatment with MLN4924 at 100 nM and 500 nM concentration for transcriptomics and proteomics analysis. RNA sequencing was utilized for dynamic transcriptomic analysis. Cell lysates were processed using bottom-up proteomics workflow and the data was acquired on a Thermo Scientific Orbitrap Fusion Lumos Tribrid mass spectrometer. Proteins were identified by querying spectral data against canonical and RNA-Seq predicted proteins and differential analysis was carried out to identify candidate determinats of vulnerability. An understanding of determinants of vulnerability to MLN4924 will expand knowledge of neddylation’s role in cancer and may point to signatures of GBM patients most likely to respond to this targeted intervention. Citation Format: Shayesteh R. Ferdosi, Brett Taylor, Nanyun Tang, Rita Bybee, Sen Peng, Victoria David-Dirgo, Krystine Garcia-Mansfield, Ritin Sharma, Patrick Pirrotte, Michael Berens, Harshil Dhruv. Dynamic multi-OMICS analysis of glioblastoma cells reveals context of vulnerability to neddylation inhibition by pevonedistat [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 248.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-248
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 6
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    Abstract 2745: Tumor microenvironment and host genetics impact glioma progression in a Collaborative Cross-based orthotopic allograft model
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2745-2745
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2745-2745
    Abstract: Gliomas are diffusely invasive brain tumors with fatal outcomes and few effective treatments. Precision medicine focuses on targeting the genetics of individual tumors, but not host genetics, despite studies that have linked germline polymorphisms with glioma risk. Accordingly, glioma survival studies in mice utilize genetically variable tumors on identical host genetic backgrounds, which fails to differentiate between cancer cell-autonomous (CCA) and tumor microenvironment (TME) effects on glioma progression and host survival. The Collaborative Cross (CC) is a panel of genetically diverse mouse strains derived from both wild- and traditional inbred laboratory strains that facilitates high-resolution genetic mapping in models of complex disease. Here, we implement a novel platform to discover genetic modifiers of both CCA and TME phenotypes using genetically defined orthotopic murine allograft gliomas and CC hosts. We stereotactically injected Nf1;Trp53-/-oligodendrocyte progenitor-derived mouse tumor cells into syngeneic C57BL/6 control mice and 14 different CC strains. Seven strains survived significantly longer than controls (P & lt;0.05), suggesting slower tumor growth (Gs, growth slow). The remaining 7 strains survived similarly to controls, suggesting fast growth (Gf, growth fast). Variable tumor growth in CC mice suggests that genetic background influences molecular processes in the TME that inhibit or potentiate tumor growth, respectively. To identify candidate genes, we performed RNA sequencing on 36 tumors from 3 Gf strains, 4 Gs strains, and controls. 134 genes were differentially expressed among Gf, Gs, and control tumors (P & lt;0.05). Hierarchical clustering on these genes revealed that Gs strains clustered separately from Gf and controls. Gene ontology analysis using GOrilla showed 30 enriched processes, (FDR q & lt;0.001), all of which were involved in immune responses or extracellular matrix biology. These results suggest that Gs strains activate immune and TME processes that slow tumor growth. Quantitative trait locus (QTL) analyses of host genetics and tumor data are pending and will facilitate identification of genetic variants that influence TME effects on tumor progression. Citation Format: Kasey Skinner, Martin Ferris, Ryan Bash, Abigail Shelton, Erin Smithberger, Steve Angus, Brian Golitz, Noah Sciaky, Jeremy Simon, Jason Stein, Glenn Matsushima, Quinn Ostrom, Lindsay Stetson, Jill Barnholtz-Sloan, Harshil Dhruv, Michael Berens, Fernando Pardo Manuel de Villena, C. Ryan Miller. Tumor microenvironment and host genetics impact glioma progression in a Collaborative Cross-based orthotopic allograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2745.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2745
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    Abstract 3757: Probing glioblastoma and its microenvironment at single cell resolution
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3757-3757
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3757-3757
    Abstract: Single-cell sequencing (scSeq) is a powerful tool to investigate cancer genomics at single cell resolution. Multiple studies have recently illuminated intratumoral heterogeneity in glioblastoma, however, the majority focused on molecular complexity of tumor cells, without taking into account unexplored host cell types that contribute to the microenvironment around GBM tumor. To address the glioblastoma microenvironment composition and potential tumor-host interactions, we performed deep coverage (176k average reads per cell) scSeq of freshly resected primary GBM patient tissue without implementing any tumor cell enrichment strategies. scSeq libraries for 902 cells were prepared using 10X Gemcode platform and sequenced on Illumina NextSeq 500. This run was of high quality with 2,663 median genes per cell and low mitochondrial gene percentage (median & lt; 5%). We used Cell Ranger analysis pipelines and Seurat packages to classify individual cells into 10 clusters and visualize them using t-SNE two-dimensional projections. We then identified the signature gene set for each cluster, relative to all other cells. Pathway analysis of each cluster signature along with known GBM microenvironment cell signatures revealed glioma tumor population along with surrounding microglia/marcophages, astrocytes, pericytes, oligodendrocytes, T cells and endothelial cells. Cell type markers identified by single cell transcriptomics were validated by IHC analysis. Microenvironmental composition and single cell signature will be confirmed through single nuclei sequencing of preserved (Frozen) tumor sample. Our results demonstrate the cellular diversity of brain tumor microenvironment and lay a foundation to further investigate the individual tumor and host cell transcriptomes that are influenced not only by their cell identity but also by their interaction with surrounding microenvironment. Citation Format: Sen Peng, Sanhita Rath, Saumya Bollam, Jenny Eschbacher, Shwetal Mehta, Nader Sanai, Michael Berens, Seungchan Kim, Harshil Dhruv. Probing glioblastoma and its microenvironment at single cell resolution [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3757.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-3757
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 8
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    Abstract 1520: Identifying differential dependency networks accounting for response to NEDD8-inhibitor in large-scale cancer cell line data
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1520-1520
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1520-1520
    Abstract: The Cancer Cell Line Encyclopedia (CCLE) houses molecular profiles of ∼800 human long term cell lines spanning several different histological types of cancer. In addition, Cancer Therapeutics Response Portal (CTRP) provides drug response measurements for 481 small molecules. Integration of these data enables investigation of the molecular correlates of drug response (sensitivity and resistance). In this current effort, we studied the NEDDylation small molecule inhibitor, MLN4924, in the context of genomic data to uncover novel mechanistic correlates of drug response across the panel of cell lines. We recently reported (Jung and Kim 2016 NAR) development of a robust computational method that shows promise to identify novel insights when applied to multi-dimensional data sets as outlined above. The Evaluation of Differential Dependency (EDDY) employs Bayesian networks to represent statistically distinct differences in relationships between genes within a specific biological pathway as queried between two conditions, in this instance, cell lines that are sensitive and those that are non-sensitive to MLN4924. While EDDY has been successfully employed in the analysis of specific diseases such as TCGA adrenocortical carcinoma, its statistical rigor incurred a prohibitive computational load to assess conditional differences across larger datasets. Recent computational enhancements to EDDY enable processing of larger datasets in reasonable time while maintaining sensitivity. The capability of analyzing broader pan-cancer datasets such as CCLE has enabled EDDY to become more capable in identifying general trends across disease subtypes. Specifically, we demonstrate the enhanced EDDY in analysis of MLN4924 response across the CCLE data set combined with CTRP data set. Initial outcomes from EDDY point to both anticipated and unanticipated biological determinants of response. For example, it is noted that specific oncogenic pathways, such as those centered on PIK3CA, appear to show differential dependencies in the sensitive and non-sensitive cell lines. We also observe genes and candidate pathways related to apoptotic mechanisms that may reveal mechanistic insights to predicting drug response. Specifically, genes and pathways associated with certain apoptotic mechanisms around mitochondrial proteins and glutathione peroxidase may serve as unique determinants of drug response. Multidimensional data analyzed by EDDY uncovers candidate mechanisms of vulnerability to specific small molecule inhibitors, which may guide development of predictive models for treatment planning when using agents with highly context-dependent efficacies. Supported by NIH U01CA168397 Citation Format: Gil Speyer, Harshil Dhruv, Jeff Kiefer, Stuart Schreiber, Paul Clemons, Michael E. Berens, Seungchan Kim. Identifying differential dependency networks accounting for response to NEDD8-inhibitor in large-scale cancer cell line data. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1520.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-1520
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 9
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    Abstract 3462: EGFRvIII-Stat5 signaling enhances glioblastoma cell invasion
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3462-3462
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3462-3462
    Abstract: Glioblastoma Multiforme (GBM) is the most common malignant brain tumor in adults. Most GBM patients succumb to the disease less than one-year post diagnosis due to the highly invasive nature of the tumor, which prevents complete surgical resection and gives rise to tumor recurrence. The invasive phenotype also confers radio and chemoresistant properties to the tumor cells; therefore, there is a need to develop new therapeutics that target drivers of GBM invasion. Amplification of EGFR is observed in over 50% of GBM tumors, of which half concurrently overexpress the variant EGFRvIII, and expression of both receptors confers a worse prognosis. EGFR and EGFRvIII cooperate to promote tumor progression and invasion, in part, through activation of the Stat-signaling pathway. Here we report that EGFRvIII activates Stat5 and GBM invasion, in part, by inducing the expression of a previously established mediator of glioma cell invasion and survival, fibroblast growth factor-inducible 14 (Fn14). EGFRvIII-mediated induction of Fn14 expression is dependent upon Stat5 and requires activation of Src, whereas EGFR regulation of Fn14 is dependent upon MEK/ERK-Stat3 activation. Notably, treatment of EGFRvIII expressing GBM cells with the FDA approved Stat5 inhibitor pimozide blocked Stat5 phosphorylation, Fn14 expression, and cell migration. Since EGFR inhibitors display limited therapeutic efficacy in GBM patients, we hypothesize that the EGFRvIII-Stat5-Fn14 signaling pathway represents a node of vulnerability in the invasive GB cell population and that targeting critical effectors in this pathway will limit GBM tumor dispersion, mitigate therapeutic resistance, and increase survival. Citation Format: Alison Roos, Harshil D. Dhruv, Sen Peng, Landon J. Inge, Serdar Tuncali, Michael Pineda, Nghia Millard, Jeffrey A. Winkles, Joseph C. Loftus, Nhan L. Tran. EGFRvIII-Stat5 signaling enhances glioblastoma cell invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3462.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3462
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 10
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    Abstract 2007: Development of a clinical assay for predicting glioblastoma (GBM) patients most likely to respond to arsenic trioxide (ATO)
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2007-2007
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2007-2007
    Abstract: Glioblastoma (GBM) is the most frequently reported primary malignant brain tumor (29.6%). The prognosis for patients who develop GBM is bleak, with average survival after diagnosis of 12-16 months. Although conventional treatment with surgery, irradiation, and temozolomide postpones tumor progression and extends patients survival, these tumors universally recur and unrelentingly result in patient death. Personalized therapies against molecular targets that drive the growth of the bulk of primary tumors have so far been unsuccessful in clinical trials, due to lack of biomarker driven approaches. Thus, there is significant unmet need to begin biomarker driven precision medicine trials for treatment of GBM. Arsenic trioxide (ATO) is an inorganic compound that induces apoptosis via multiple pathways. Arsenic trioxide (TRISENOX®) is approved by the FDA for patients with acute promyelocytic leukemia (APL). Pre-clinical studies in brain tumors suggest that ATO is synergistic with radiation therapy (RT) and may enhance effects of radiation. In an earlier Phase II clinical trial (NCT00275067) using intravenous ATO and temozolomide in combination with radiation therapy for patients with newly diagnosed malignant gliomas, a subset of patients demonstrated notable benefit (Progression free survival (avg. = 638 days) and overall survival (avg. = 967 days)). Comparing RNAseq data from preclinical models and specimen from the Phase II clinical trial, the responder group could be confidently distinguished from the non-responder cohort leading to gene signatures of differential ATO sensitivity. Applying a Relative Expression Ordering (REO) Analysis framework, we pinpointed a probability-based roster of 28 top scoring pairs (TSP) as the classifier by which to identify patients with a higher likelihood to benefit from including ATO in combination with TMZ and radiation. This method is completely independent of platform on which data is collected and can be used for analysis of individual, newly-enrolled, n = 1 patients. We are advancing a protocol using the above gene classifier as enrollment criteria for an Adaptive clinical trial testing an oral formulation of ATO for newly diagnosed IDH1 WT Primary GBM patients; the trial will test whether patients whose tumors with ATO Classifier show 6-month PFS benefit by addition of ATO to Standard-of-Care. The trial will validate and refine the comprehensive biomarker panel that could identify most likely GBM responders to ATO and TMZ treatment in combination with radiation. Supported by a grant from the Baylor Scott & White Foundation. Citation Format: Sen Peng, Jinghua Gu, Xuan Wang, Sanhita Rath, Jacob Cardenas, Nicholas Schork, George Snipes, Harshil Dhruv, Karen Fink, Michael Berens. Development of a clinical assay for predicting glioblastoma (GBM) patients most likely to respond to arsenic trioxide (ATO) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2007.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-2007
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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