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  • American Association for Cancer Research (AACR)  (3)
  • 1
    Online Resource
    Online Resource
    Identification of Patients with Recurrent Glioblastoma Who May Benefit from Combined Bevacizumab and CCNU Therapy: A Report from the BELOB Trial
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 3 ( 2016-02-01), p. 525-534
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 3 ( 2016-02-01), p. 525-534
    Abstract: The results from the randomized phase II BELOB trial provided evidence for a potential benefit of bevacizumab (beva), a humanized monoclonal antibody against circulating VEGF-A, when added to CCNU chemotherapy in patients with recurrent glioblastoma (GBM). In this study, we performed gene expression profiling (DASL and RNA-seq) of formalin-fixed, paraffin-embedded tumor material from participants of the BELOB trial to identify patients with recurrent GBM who benefitted most from beva+CCNU treatment. We demonstrate that tumors assigned to the IGS-18 or “classical” subtype and treated with beva+CCNU showed a significant benefit in progression-free survival and a trend toward benefit in overall survival, whereas other subtypes did not exhibit such benefit. In particular, expression of FMO4 and OSBPL3 was associated with treatment response. Importantly, the improved outcome in the beva+CCNU treatment arm was not explained by an uneven distribution of prognostically favorable subtypes as all molecular glioma subtypes were evenly distributed along the different study arms. The RNA-seq analysis also highlighted genetic alterations, including mutations, gene fusions, and copy number changes, within this well-defined cohort of tumors that may serve as useful predictive or prognostic biomarkers of patient outcome. Further validation of the identified molecular markers may enable the future stratification of recurrent GBM patients into appropriate treatment regimens. Cancer Res; 76(3); 525–34. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-15-0776
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
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    Online Resource
    Abstract 6140: Transcriptional evolution of glioblastoma reveals changes in bulk composition, mesenchymal sub-type as end-state, and a prognostic association with increased extracellular matrix gene expression
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6140-6140
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6140-6140
    Abstract: Background: Glioblastoma is the most prevalent and severe type of malignant brain tumor in adults. Although the genetic make-up initiating glioblastoma is increasingly better understood, a better understanding in the mechanisms that drive its evolution, heterogeneity and therapy resistance may reveal new directions for therapy development. To get better insights into glioblastoma evolution, we analyzed and de-convoluted transcriptomes of primary and recurrent glioblastoma resections. Material and Methods: Matching primary and secondary resections from n=185 glioblastoma patients were collected as part of EORTC Study 1542. The study was extended with tumor pairs from n=51 patients from the international GLASS study. The datasets were subjected to differential and deconvolution analysis using in-house algorithms. Results: When mapping the tumor samples into a reduced Glioblastoma Intrinsic Transcriptional Subtype space, we visualized subtype traversal, indicating that the CL subtype most often switches. As we found no more transitions from MES to other subtypes than to be expected by chance, we concluded that MES is an end-state. On average, tumor cell percentages decreased from ~67% to ~50% mostly due to an increase in TAM/microglia. Differential expression analysis was performed with correction for tumor cell percentages. While expression of most known oncogenes did not change considerably over time, marker genes of TAM/microglia, neurons and oligodendrocytes were up-regulated whereas endothelial cell markers were down-regulated over time. Furthermore, a cluster of ~30 extracellular matrix-associated genes increase significantly over time. A signature representing the gene-set was significantly associated with poor survival; high signatures were in particular associated to survival in secondary resections (P = 6.613e-06, Kaplan-Meier estimator). This suggests that the increase of extracellular matrix expression fulfils an important role in glioblastoma evolution. Conclusion: Using a large cohort, we interrogated changes in the glioblastoma transcriptome over time and found that in particular the composition of the tumor and its environment changes. The tumor cell percentage drops, suggesting more invasion or recruitment of non-malignant cells or a combination of both. This change is independent of an increase in the prognostic increase in extracellular matrix expression. Citation Format: Youri Hoogstrate, Kaspar Draaisma, Santoesha A. Ghisai, Iris de Heer, Levi van Hijfte, Wouter Coppieters, Melissa Kerkhof, Astrid Weyerbrock, Marc Sanson, Ann Hoeben, Slávka Lukacova, Giuseppe Lombardi, Sieger Leenstra, Monique Hanse, Ruth Fleischeuer, Colin Watts, Joseph McAbee, Nicos Angelopoulos, Thierry Gorlia, Vassilis Golfinopoulos, Johan M. Kros, Vincent Bours, Martin J. van den Bent, Pierre A. Robe, Pim J. French. Transcriptional evolution of glioblastoma reveals changes in bulk composition, mesenchymal sub-type as end-state, and a prognostic association with increased extracellular matrix gene expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6140.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-6140
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    detail.hit.zdb_id: 410466-3
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  • 3
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    Online Resource
    Abstract 3568: CYP3A4 epoxygenase activity mediates ER+ mammary tumor growth and angiogenesis, in part, through EET biosynthesis and is inhibited by biguanides
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3568-3568
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3568-3568
    Abstract: While cytochrome P450 enzymes (CYPs) are implicated in tumor angiogenesis through biosynthesis of epoxyeicosatrienoic acids (EETs), little is known about breast cancer cell-intrinsic CYPs that exhibit epoxygenase activity, such as CYP3A4. In an orthotopic breast cancer model, silencing of epithelial CYP3A4 suppressed angiogenesis-related escape of ER+ breast tumors from dormancy. While the diabetes drug metformin inhibits mitochondrial complex I and inhibits tumor growth, how it does so is unknown. Metformin inhibited CYP epoxygenase activity and co-crystallized in the active site of CYP3A4, hydrogen bonding with arginine 212, allowing the development of hexyl-benzyl-biguanide (HBB) as a CYP3A4 inhibitor using molecular modeling. HBB exhibited more than 10-fold greater potency than metformin for inhibition of ER+ mammary tumor growth and inhibited associated tumor angiogenesis. HBB inhibited EET biosynthesis ∼40-fold more potently than metformin and was ∼40-fold more potent for activation of AMPK phosphorylation. EETs suppressed and CYP silencing promoted AMPK phosphorylation, linking CYPs with AMPK regulation in breast cancer. HBB depolarized mitochondria, reduced oxygen consumption rates and suppressed the Warburg effect, while EETs restored the mitochondrial membrane potential. CYP3A4 silencing and HBB treatment increased reactive oxygen species (ROS) production, suggesting that CYPs suppress cancer cell death, in part, through suppression of ROS. CYP3A4 silencing sensitized breast cancer cells to hormonal therapy and chemotherapy, abrogated by EETs. Because EETs are autocrine, paracrine and endocrine, these results implicate CYPs in tumor growth, in part, through cell-cell mediation of mitochondrial homeostasis and demonstrate the potential of CYP3A4 as a therapeutic target in breast cancer. Citation Format: Zhijun Guo, Irina F. Sevrioukova, Eric Hanse, Ilia Denisov, Xia Zhang, Ting-Lan Chiu, Daniel Swedien, Justin Stamschror, Juan Alvarez, William Marerro Ortiz, Monique Morgan, Michael Maher, Kathryn J. Chavez, Dafydd Thomas, Young Kyung Bae, Jonathan Henriksen, Beverly Norris, Robert J. Schumacher, Henry Wang, Robin Bliss, Haitao Chu, Rebecca Cuellar, Thomas L. Poulos, Stephen G. Sligar, William Atkins, Stephen Schmechel, Jorge Capdevila, John Falck, Ian Blair, Jeffrey P. Jones, Gunda Georg, Kalpna Gupta, Ameeta Kelekar, Elizabeth Amin, David A. Potter. CYP3A4 epoxygenase activity mediates ER+ mammary tumor growth and angiogenesis, in part, through EET biosynthesis and is inhibited by biguanides. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3568. doi:10.1158/1538-7445.AM2015-3568
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-3568
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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