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  • American Association for Cancer Research (AACR)  (9)
  • Medicine  (9)
  • 1
    Online Resource
    Online Resource
    Metabolic Imaging of the Human Brain with Hyperpolarized 13C Pyruvate Demonstrates 13C Lactate Production in Brain Tumor Patients
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 14 ( 2018-07-15), p. 3755-3760
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 14 ( 2018-07-15), p. 3755-3760
    Abstract: Hyperpolarized (HP) MRI using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here, we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. In vivo production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, whereas production of HP lactate in the entire brain was likely due to baseline metabolism. We correlated our results with standard clinical brain MRI, MRI DCE perfusion, and in one case FDG PET/CT. Our results suggest that HP 13C pyruvate-to-lactate conversion may be a viable metabolic biomarker for assessing tumor response. Significance: Hyperpolarized pyruvate MRI enables metabolic imaging in the brain and can be a quantitative biomarker for active tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3755/F1.large.jpg. Cancer Res; 78(14); 3755–60. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-18-0221
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
    Online Resource
    Online Resource
    Tumor-Infiltrating Lymphocytes in Glioblastoma Are Associated with Specific Genomic Alterations and Related to Transcriptional Class
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 18 ( 2013-09-15), p. 4951-4960
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 18 ( 2013-09-15), p. 4951-4960
    Abstract: Purpose: Tumor-infiltrating lymphocytes (TIL) have prognostic significance in many cancers, yet their roles in glioblastoma have not been fully defined. We hypothesized that TILs in glioblastoma are associated with molecular alterations, histologies, and survival. Experimental Design: We used data from The Cancer Genome Atlas (TCGA) to investigate molecular, histologic, and clinical correlates of TILs in glioblastomas. Lymphocytes were categorized as absent, present, or abundant in histopathologic images from 171 TCGA glioblastomas. Associations were examined between lymphocytes and histologic features, mutations, copy number alterations, CpG island methylator phenotype, transcriptional class, and survival. We validated histologic findings using CD3G gene expression. Results: We found a positive correlation between TILs and glioblastomas with gemistocytes, sarcomatous cells, epithelioid cells, and giant cells. Lymphocytes were enriched in the mesenchymal transcriptional class and strongly associated with mutations in NF1 and RB1. These mutations are frequent in the mesenchymal class and characteristic of gemistocytic, sarcomatous, epithelioid, and giant cell histologies. Conversely, TILs were rare in glioblastomas with small cells and oligodendroglioma components. Lymphocytes were depleted in the classical transcriptional class and in EGF receptor (EGFR)-amplified and homozygous PTEN-deleted glioblastomas. These alterations are characteristic of glioblastomas with small cells and glioblastomas of the classical transcriptional class. No association with survival was shown. Conclusions: TILs were enriched in glioblastomas of the mesenchymal class, strongly associated with mutations in NF1 and RB1 and typical of histologies characterized by these mutations. Conversely, TILs were depleted in the classical class, EGFR-amplified, and homozygous PTEN-deleted tumors and rare in histologies characterized by these alterations. Clin Cancer Res; 19(18); 4951–60. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-0551
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 2036787-9
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  • 3
    Online Resource
    Online Resource
    Double Minute Chromosomes in Glioblastoma Multiforme Are Revealed by Precise Reconstruction of Oncogenic Amplicons
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 19 ( 2013-10-01), p. 6036-6045
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 19 ( 2013-10-01), p. 6036-6045
    Abstract: DNA sequencing offers a powerful tool in oncology based on the precise definition of structural rearrangements and copy number in tumor genomes. Here, we describe the development of methods to compute copy number and detect structural variants to locally reconstruct highly rearranged regions of the tumor genome with high precision from standard, short-read, paired-end sequencing datasets. We find that circular assemblies are the most parsimonious explanation for a set of highly amplified tumor regions in a subset of glioblastoma multiforme samples sequenced by The Cancer Genome Atlas (TCGA) consortium, revealing evidence for double minute chromosomes in these tumors. Further, we find that some samples harbor multiple circular amplicons and, in some cases, further rearrangements occurred after the initial amplicon-generating event. Fluorescence in situ hybridization analysis offered an initial confirmation of the presence of double minute chromosomes. Gene content in these assemblies helps identify likely driver oncogenes for these amplicons. RNA-seq data available for one double minute chromosome offered additional support for our local tumor genome assemblies, and identified the birth of a novel exon made possible through rearranged sequences present in the double minute chromosomes. Our method was also useful for analysis of a larger set of glioblastoma multiforme tumors for which exome sequencing data are available, finding evidence for oncogenic double minute chromosomes in more than 20% of clinical specimens examined, a frequency consistent with previous estimates. Cancer Res; 73(19); 6036–45. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-13-0186
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 4
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    Online Resource
    Abstract 4627: Role of intratumoral cell heterogeneity on therapeutic efficacy in glioblastoma.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4627-4627
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4627-4627
    Abstract: Glioblastoma (GBM), the most common and lethal malignancy of the brain, is typified by high degrees of histologic and molecular heterogeneity. The majority of GBM harbor amplification and/or mutations of receptor tyrosine kinases (RTKs), most frequently EGFR (40-50%) or PDGFRA (∼15%). We recently documented that a subset of glioblastoma harbors independent focal amplification of two or more RTKs, most commonly PDGFRA and EGFR. This phenomenon lends genetic evidence to support that co-expression of more than one RTK in the same cell serves a functional purpose in conferring selective growth advantage to GBM. In this study we demonstrate that EGF stimulates endogenous interaction between activated EGFR and PDGFRA, assessed using reciprocal coimmunoprecipitation and proximity ligation assays in patient-derived GBM tumor-sphere lines of multiple genotypes. EGF leads to phosphorylation of PDGFRA Y720. This transactivation and subsequent activation of Shp2 are abolished by EGFR inhibitors gefitinib or lapatinib at low concentrations. Evidence of EGFR-PDGFRA interaction was found in the majority of GBM tumorsphere lines where both receptors were expressed. We used multichannel phospho-FACS in a panel of tumorsphere lines to characterize the cell-to-cell heterogeneity of EGFR and PDGFRA expression levels and how these levels affect p-Akt and p-ERK baseline activity, response to ligands and response to targeted receptor inhibition. Indeed, high expression of both EGFR and PDGFRA identifies tumor cells with elevated MAPK and PI3K pathway activity. Notably, these tumor cells have high downstream pathway activation in the absence of explicit stimulation by ligand and appear to be refractory to dual RTK inhibition. Taken together, these data underscore the role of tumor cell RTK heterogeneity in therapeutic resistance to RTK inhibitors in GBM. This study also highlights a possible mechanism that heterotypic RTKs in the same cell may utilize to achieve growth advantage. Citation Format: Debyani Chakravarty, Alicia Pedraza, Angela H. Liu, Jesse Cotari, Grégoire Altan-Bonnet, Cameron W. Brennan. Role of intratumoral cell heterogeneity on therapeutic efficacy in glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4627. doi:10.1158/1538-7445.AM2013-4627
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-4627
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
    Online Resource
    Genomic Correlates of Disease Progression and Treatment Response in Prospectively Characterized Gliomas
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 18 ( 2019-09-15), p. 5537-5547
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 18 ( 2019-09-15), p. 5537-5547
    Abstract: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood. Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. Results: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P & lt; 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. Conclusions: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-19-0032
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 2036787-9
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  • 6
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    Online Resource
    Candidate Pathways for Promoting Differentiation or Quiescence of Oligodendrocyte Progenitor-like Cells in Glioma
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 18 ( 2012-09-15), p. 4856-4868
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 18 ( 2012-09-15), p. 4856-4868
    Abstract: Platelet-derived growth factor receptor alpha–positive oligodendrocyte progenitor cells (OPC) located within the mature central nervous system may remain quiescent, proliferate, or differentiate into oligodendrocytes. Human glioblastoma multiforme tumors often contain rapidly proliferating oligodendrocyte lineage transcription factor 2 (Olig2)-positive cells that resemble OPCs. In this study, we sought to identify candidate pathways that promote OPC differentiation or quiescence rather than proliferation. Gene expression profiling conducted in both normal murine OPCs and highly proliferative Olig2-positive glioma cells identified all the transcripts associated with the highly proliferative state of these cells and showed that among the various cell types found within the brain, Olig2-positive tumor cells are most similar to OPCs. We then subtracted OPC transcripts found in tumor samples from those found in normal brain samples and identified 28 OPC transcripts as candidates for promoting differentiation or quiescence. Systematic analysis of human glioma data revealed that these genes have similar expression profiles in human tumors and were significantly enriched in genomic deletions, suggesting an antiproliferative role. Treatment of primary murine glioblastoma cells with agonists of one candidate gene, Gpr17, resulted in a decreased number of neurospheres. Together, our findings show that comparison of the molecular phenotype of progenitor cells in tumors to the equivalent cells in the normal brain represents a novel approach for the identification of targeted therapies. Cancer Res; 72(18); 4856–68. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-11-2632
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 7
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    Phase II Study of Bevacizumab, Temozolomide, and Hypofractionated Stereotactic Radiotherapy for Newly Diagnosed Glioblastoma
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 19 ( 2014-10-01), p. 5023-5031
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 19 ( 2014-10-01), p. 5023-5031
    Abstract: Purpose: Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab. Experimental Design: Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1. Results: Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84–100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P & lt; 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT. Conclusions: This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non–IDH-1–mutated glioblastoma. Clin Cancer Res; 20(19); 5023–31. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-0822
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 8
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    Ultrasmall Core-Shell Silica Nanoparticles for Precision Drug Delivery in a High-Grade Malignant Brain Tumor Model
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 1 ( 2020-01-01), p. 147-158
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 1 ( 2020-01-01), p. 147-158
    Abstract: Small-molecule inhibitors have revolutionized treatment of certain genomically defined solid cancers. Despite breakthroughs in treating systemic disease, central nervous system (CNS) metastatic progression is common, and advancements in treating CNS malignancies remain sparse. By improving drug penetration across a variably permeable blood–brain barrier and diffusion across intratumoral compartments, more uniform delivery and distribution can be achieved to enhance efficacy. Experimental Design: Ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), were functionalized with αv integrin-binding (cRGD), or nontargeting (cRAD) peptides, and PET labels (124I, 89Zr) to investigate the utility of dual-modality cRGD-C' dots for enhancing accumulation, distribution, and retention (ADR) in a genetically engineered mouse model of glioblastoma (mGBM). mGBMs were systemically treated with 124I-cRGD- or 124I-cRAD-C' dots and sacrificed at 3 and 96 hours, with concurrent intravital injections of FITC-dextran for mapping blood–brain barrier breakdown and the nuclear stain Hoechst. We further assessed target inhibition and ADR following attachment of dasatinib, creating nanoparticle–drug conjugates (Das-NDCs). Imaging findings were confirmed with ex vivo autoradiography, fluorescence microscopy, and p-S6RP IHC. Results: Improvements in brain tumor delivery and penetration, as well as enhancement in the ADR, were observed following administration of integrin-targeted C' dots, as compared with a nontargeted control. Furthermore, attachment of the small-molecule inhibitor, dasatinib, led to its successful drug delivery throughout mGBM, demonstrated by downstream pathway inhibition. Conclusions: These results demonstrate that highly engineered C' dots are promising drug delivery vehicles capable of navigating the complex physiologic barriers observed in a clinically relevant brain tumor model.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-19-1834
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 9
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    Suppression of MicroRNA-9 by Mutant EGFR Signaling Upregulates FOXP1 to Enhance Glioblastoma Tumorigenicity
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 5 ( 2014-03-01), p. 1429-1439
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 5 ( 2014-03-01), p. 1429-1439
    Abstract: The EGF receptor (EGFR) is amplified and mutated in glioblastoma, in which its common mutation (ΔEGFR, also called EGFRvIII) has a variety of activities that promote growth and inhibit death, thereby conferring a strong tumor-enhancing effect. This range of activities suggested to us that ΔEGFR might exert its influence through pleiotropic effectors, and we hypothesized that microRNAs might serve such a function. Here, we report that ΔEGFR specifically suppresses one such microRNA, namely miR-9, through the Ras/PI3K/AKT axis that it is known to activate. Correspondingly, expression of miR-9 antagonizes the tumor growth advantage conferred by ΔEGFR. Silencing of FOXP1, a miR-9 target, inhibits ΔEGFR-dependent tumor growth and, conversely, de-repression of FOXP1, as a consequence of miR-9 inhibition, increases tumorigenicity. FOXP1 was sufficient to increase tumor growth in the absence of oncogenic ΔEGFR signaling. The significance of these findings is underscored by our finding that high FOXP1 expression predicts poor survival in a cohort of 131 patients with glioblastoma. Collectively, these data suggest a novel regulatory mechanism by which ΔEGFR suppression of miR-9 upregulates FOXP1 to increase tumorigenicity. Cancer Res; 74(5); 1429–39. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-13-2117
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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