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  • American Association for Cancer Research (AACR)  (81)
  • 1
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    Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 3 ( 2014-02-01), p. 852-861
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 3 ( 2014-02-01), p. 852-861
    Kurzfassung: A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P & lt; 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-13-1051
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2014
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
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    Abstract B077: Comprehensive molecular characterization and high-throughput chemical screening identifies genetic dependencies and molecular vulnerabilities in glioblastoma cell line models
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. B077-B077
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. B077-B077
    Kurzfassung: Introduction: Glioblastoma (GBM) is a lethal disease without effective treatments. To advance toward effective therapeutic approaches that are biomarker driven, we need new targeted agents and to develop accurate preclinical cell line models that encompass its cellular and molecular diversity. Experimental Procedures: To identify molecular targets and therapies we profiled across 78 GBM cell lines 381 drugs described in the Cancer Therapeutics Response Portal (CTRP) at 16 different duplicated concentrations. The cell lines consisted of two different models: patient-derived GBM cell lines (PDGCL) and long-term GBM cell lines (LTGCL), the latter of which were previously included in the Cancer Cell Line Encyclopedia (CCLE). Comprehensive characterization of copy number changes, mutations (whole exome sequencing), gene and protein expression was performed. After integrating and correlating systematically molecular alterations with drug sensitivities we yielded 7,948,422 pharmacogenomic interactions. Results: PDGCLs preserve neural and glial marker heterogeneity and exhibit all allelic imbalances seen in human GBMs better than in LTGCLs. All genes known to undergo frequent ( & gt;5%) driver mutations among GBMs exhibited at least one mutation among cell lines, with the exception of IDH1. PDGCLs enrich for the proneural molecular phenotype while LTGCL models exhibit mesenchymal expression programs. Among pharmacogenomic interactions NAMPT inhibitors were one of the most active compounds and revealed dependencies associated with enzymatic activities. Cell lines TP53 wild type, overexpressing CDKN1A and OLIG2 were sensitive to MDM2 inhibitors (Nutlins). Testing new MDM2 inhibitors validate “in vitro” previous findings, show increased drug potency, and block tumor growth in intracranial xenografts models. TP53 mutant lines exhibit a lower overall response to the panel of 381 targeted drugs. However, simultaneous genetic disruption of TP53, CDKN2A, and CHK2 trigger a synthetic lethal interaction. The CHK1/2 chemical inhibitor results were phenocopied by shRNA suppression of CHK2. Furthermore, response to chemical inhibitors of proteins involved in G2M checkpoint (ATM/ATR, WEE1, and CDK1 inhibitors) was significantly correlated with response to a CHK1/2 inhibitor. AZD-7762 response and predictive genotypes were associated by gene set enrichments related with E2F targets and G2M checkpoint. Next we identified vulnerabilities involving mutually exclusive complementary functional associations. Mutations in different genes of the PI3K holo-enzyme complex predict sensitivity to a PIK3 inhibitor. Our results suggest that associations between genomic features and response to monotherapies can help to identify effective drug combinations in biomarker-defined subpopulations. As proof of concept we found that proper combination of rationally targeted anticancer therapies displays synergistic effects in right genetic context and the specific molecular insults. Conclusion: Our analyses suggest pharmacologic strategies for genetic subgroups of GBMs and provide molecular insights to drive targeted therapies in the new era of precision medicine. Citation Format: Ruben Ferrer-Luna, Shakti H. Ramkissoon, Lori A. Ramkissoon, Kristine Pellton, Steven E. Schumacher, Rebecca Lamothe, Jaime H. Cheah, Sam Haidar, Yun J. Kang, David S. Knoff, Cecile L. Maire, Karl H. Olausson, Wenyu Song, Ahmed Idbaih, Mikael L. Rinne, David A. Reardon, Patrick Y. Wen, Paul A. Clemons, Stuart L. Schreiber, Alykhan J. Shamji, Rameen Beroukhim, Keith L. Ligon. Comprehensive molecular characterization and high-throughput chemical screening identifies genetic dependencies and molecular vulnerabilities in glioblastoma cell line models [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 B077.
    Materialart: Online-Ressource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-B077
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2018
    ZDB Id: 2062135-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
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    Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 23, No. 7 ( 2014-07-01), p. 1421-1427
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 23, No. 7 ( 2014-07-01), p. 1421-1427
    Kurzfassung: Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P & lt; 2.5 × 10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 × 10−6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56–0.82; P = 2.33 × 10−5). Other associations of note included TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 × 10−5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26–0.73; P = 4.56 × 10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.
    Materialart: Online-Ressource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-13-0962
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2014
    ZDB Id: 2036781-8
    ZDB Id: 1153420-5
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
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    Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Immunology Research Vol. 2, No. 4 ( 2014-04-01), p. 332-340
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 2, No. 4 ( 2014-04-01), p. 332-340
    Kurzfassung: The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.
    Materialart: Online-Ressource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-13-0136
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2014
    ZDB Id: 2732517-9
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
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    Abstract 4974: Pharmacogenomic interactions in glioblastoma cell line models
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4974-4974
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4974-4974
    Kurzfassung: Glioblastoma (GBM) is the most common and malignant brain tumor. These tumors display a uniform and very short survival time even with treatment, but are highly heterogeneous at the histological and genomic level. To identify effective treatments and dependencies, we profiled the sensitivity of a panel of cancer cell lines to a small molecules and integrated this with systematic analysis of genetic and non-genetic determinants associated with chemical response. Methods. We profiled 381 drugs described in the Cancer Therapeutics Response Portal (CTRP) at 16 different duplicated concentrations across 78 GBM cell lines belonging to two different models: Patient-Derived GBM Cell Lines (PDGCL) and Long-Term GBM Cell Lines (LTGCL) previously included in the Cancer Cell Line Encyclopedia (CCLE). Cell lines were deeply characterized as to genotype and phenotype. As non-genomic determinants we considered: model, growth rate, behavior, stem cell and differentiation markers. Genomic determinants included mutations and somatic copy number alterations (SCNA) computed from whole exome sequencing. Each of these were integrated to determine oncogene and tumor suppressor gene pathway disruption (p53, RB and RTK signaling). At transcriptomic level we considered expression of 20.647 genes and patters described in GBMs (proneural, neural, classical, mesenchymal). Overall we correlated 10,859,643 pharmacogenomic features to discover associations with drug sensitivity. Summary. We developed a brain tumor living tissue bank as platform for preclinical pharmacogenomics analysis. Large-scale phenotypic characterization of GBM models showed increased cellular and molecular heterogeneity among PDGCLs compared to LTGCLs. PDGCLs better recapitulated patient GBM copy-number profiles. GBM cell lines exhibited all major driver mutations in human GBMs, except IDH1. PDGCLs and LTGCLs enriched for proneural and mesenchymal phenotypes, respectively. We identified NAMPT inhibitors as among the compounds with highest activity across cell lines. Integrative pharmacogenomic analyses showed MDM2/4 inhibitors were able to effectively suppress TP53 wild type GBM models, being CDKN1A (p21) expression a robust predictor of drug response in vitro and in vivo. Overall drug resistance across the screen in lines was highly associated with TP53 mutation, however a specific subset of TP53 mutant cell lines bearing simultaneous CDKN2A/B deletions were sensitive to CHK1/2 inhibitors, revealing a potential synthetic lethal interaction of clinical significance in these highly refractory cells. Analysis identified genetic alterations associated with vulnerabilities targeted by small molecules. About 85% of GBM patients display p53 pathway disruption, our results suggest independent pharmacological strategies for two genetic subtypes of GBM determined by TP53 and CDKN1A status. Our analyses provide molecular insights to drive targeted therapies in the new era of precision medicine. Citation Format: Ruben Ferrer-Luna, Shakti H. Ramkissoon, Karl H. Olausson, Lori A. Ramkissoon, Steven Schumacher, Rebecca Lamothe, Jaime H. Cheah, Kristine Pellton, Sam Haidar, Yun J. Kang, Brenton R. Paolella, Cecile Maire, Wenyu Song, Alice Meng, Ahmed Idbaih, Mikael L. Rinne, David A. Reardon, Patrick Y. Wen, Paul A. Clemons, Stuart L. Schreiber, Alykhan F. Shamji, Rameen Beroukhim, Keith L. Ligon. Pharmacogenomic interactions in glioblastoma cell line models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Canc er Res 2017;77(13 Suppl):Abstract nr 4974. doi:10.1158/1538-7445.AM2017-4974
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-4974
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2017
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
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    Abstract B051: PDX-derived and patient-derived prostate cancer organoids as a clinically relevant platform for translational research
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 16_Supplement ( 2018-08-15), p. B051-B051
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 16_Supplement ( 2018-08-15), p. B051-B051
    Kurzfassung: Metastatic castration-resistant prostate cancer (CRPC) is a genetically heterogeneous disease. Effective translational research demands a diverse and representative set of preclinical models. A major obstacle in the field is the limited capacity to culture prostate cancer-derived cells in vitro. Few cell lines exist. Those that are available do not well represent the genetic diversity of the disease, nor do they accurately predict in vivo response. Recently, organoid culture techniques developed in the Sawyers and Clevers laboratories have increased our ability to grow metastatic tumor-derived prostate cancer cells in vitro. This represents a great step forward, but is restricted by limited availability of tissue and a success rate of & lt;20% when establishing new lines. In the field of prostate cancer, patient-derived xenograft (PDX) lines are a model that broadly represents the clinical and genetic diversity of the disease. Like primary prostate tumors, PDXs have not been readily adaptable to in vitro culture (including the standard organoid method), making them poorly suited for mechanistic studies or high-throughput drug screens. Therefore, there is great interest in adapting the prostate cancer PDX model to an in vitro culture system. The LuCaP series of PDXs is a well-characterized set of ~40 diverse prostate cancer specimens. Using LuCaP PDXs, we systematically tested several modifications to the organoid culture method. This includes the addition of factors to modify metabolism, growth, and differentiation; removal of standard media components; and combinations thereof. We show that p38 is required for growth and survival of almost all the LuCaP organoids. Removal of the p38 inhibitor component from standard prostate organoid media improves initial growth and makes it possible to maintain many PDX-derived organoids over several generations. Additional modifications to individual LuCaP culture conditions improve growth. We successfully cultured 21 of 24 different LuCaPs attempted, for at least one generation, and 10 have been grown long-term. We show that PDX-derived organoids recapitulate the phenotype of the original PDX tumor, including AR-dependent growth. For example, we have shown that homologous recombination deficient LuCaP organoid responses to olaparib reflect the enhanced sensitivity seen for patients in clinical trials. Additionally, our method improves the success rate for culturing samples directly from patient biopsies. We show that 2 of 3 biopsy-derived organoid lines that we have established grow well in our conditions but not in standard published conditions. The third grows equally well in both. Further, our data suggest that p38 is a previously unappreciated target for CRPC treatment. Importantly, our work immediately and significantly increases the number of prostate cancer lines available to the community by making the LuCaP PDXs accessible to in vitro culture, and by improving the success rate for establishing organoids directly from patient samples. Citation Format: Michael L. Beshiri, Caitlin M. Tice, Crystal Tran, Holly M. Nguyen, Adam G. Sowalsky, Supreet Agarwal, Keith H. Jansson, Kerry McGowen, Aian Neil Alilin, JuanJuan Yin, Fatima H. Karzai, William L. Dahut, Eva Corey, Kathleen Kelly. PDX-derived and patient-derived prostate cancer organoids as a clinically relevant platform for translational research [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B051.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PRCA2017-B051
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2018
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
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  • 7
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    Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy
    American Association for Cancer Research (AACR) ; 2023
    In:  Blood Cancer Discovery Vol. 4, No. 2 ( 2023-03-01), p. 118-133
    Details
    In: Blood Cancer Discovery, American Association for Cancer Research (AACR), Vol. 4, No. 2 ( 2023-03-01), p. 118-133
    Kurzfassung: We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)–negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T-cell therapy in early lines of MM treatment. Significance: CAR T cells in early lines of MM therapy could be safer and more effective than in the advanced setting, where prior studies have focused. We evaluated the safety, pharmacokinetics, and efficacy of CAR T cells in patients with low disease burden, responding to current therapy, combined with standard maintenance therapy. This article is highlighted in the In This Issue feature, p. 101
    Materialart: Online-Ressource
    ISSN: 2643-3230 , 2643-3249
    URL: Article
    DOI: 10.1158/2643-3230.BCD-22-0074
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2023
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  • 8
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    BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Discovery ( 2022-11-11), p. OF1-OF26
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), ( 2022-11-11), p. OF1-OF26
    Kurzfassung: Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell–like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas. Significance: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1–BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma.
    Materialart: Online-Ressource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-21-1491
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2022
    ZDB Id: 2607892-2
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  • 9
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    Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Immunology Research Vol. 4, No. 2 ( 2016-02-01), p. 124-135
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 4, No. 2 ( 2016-02-01), p. 124-135
    Kurzfassung: Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules, including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single-agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single-agent anti–PD-1, anti–PD-L1, or anti–CTLA-4 therapy in 50%, 20%, and 15% of treated animals, respectively. Combination therapy of anti–CTLA-4 plus anti–PD-1 cured 75% of the animals, even against advanced, later-stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor rechallenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8+ and natural killer cells and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma. Cancer Immunol Res; 4(2); 124–35. ©2015 AACR.
    Materialart: Online-Ressource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-15-0151
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2016
    ZDB Id: 2732517-9
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
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    A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 17 ( 2018-09-01), p. 4332-4345
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 17 ( 2018-09-01), p. 4332-4345
    Kurzfassung: Purpose: Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models that represent the genomic landscape of clinical disease. Metastatic castrate-resistant prostate cancer (mCRPC) patient-derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high-throughput and mechanistic analysis. Experimental Design: Using 20 models from the LuCaP mCRPC PDX cohort, including adenocarcinoma and neuroendocrine lineages, we systematically tested & gt;20 modifications to prostate organoid conditions. Organoids were evaluated for genomic and phenotypic stability and continued reliance on the AR signaling pathway. The utility of the platform as a genotype-dependent model of drug sensitivity was tested with olaparib and carboplatin. Results: All PDX models proliferated as organoids in culture. Greater than 50% could be continuously cultured long-term in modified conditions; however, none of the PDXs could be established long-term as organoids under previously reported conditions. In addition, the modified conditions improved the establishment of patient biopsies over current methods. The genomic heterogeneity of the PDXs was conserved in organoids. Lineage markers and transcriptomes were maintained between PDXs and organoids. Dependence on AR signaling was preserved in adenocarcinoma organoids, replicating a dominant characteristic of CRPC. Finally, we observed maximum cytotoxicity to the PARP inhibitor olaparib in BRCA2−/− organoids, similar to responses observed in patients. Conclusions: The LuCaP PDX/organoid models provide an expansive, genetically characterized platform to investigate the mechanisms of pathogenesis as well as therapeutic responses and their molecular correlates in mCRPC. Clin Cancer Res; 24(17); 4332–45. ©2018 AACR.
    Materialart: Online-Ressource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-0409
    RVK:
    XA 36791
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2018
    ZDB Id: 1225457-5
    ZDB Id: 2036787-9
    Standort Signatur Einschränkungen Verfügbarkeit
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