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  • American Association for Cancer Research (AACR)  (10)
  • 1
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    Abstract P041: Initial results from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide in patients with metastatic prostate cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Molecular Cancer Therapeutics Vol. 20, No. 12_Supplement ( 2021-12-01), p. P041-P041
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 20, No. 12_Supplement ( 2021-12-01), p. P041-P041
    Abstract: Background: Upregulation of the glucocorticoid receptor (GR) is a potential mechanism of resistance to enzalutamide and other androgen receptor (AR) modulators in prostate cancer. Preclinical studies have demonstrated that GR activation can bypass enzalutamide-mediated AR inhibition and support prostate cancer cell growth. Overexpression of GR is associated with poor outcomes in castration-resistant prostate cancer patients (CRPC) treated with enzalutamide. ORIC-101 is a potent and selective orally bioavailable, small molecule antagonist of GR. Mechanistically, ORIC-101 inhibits GR transcriptional activity and blocks the pro-survival signals mediated by the activated nuclear hormone receptor. Methods: A modified interval 3+3 (i3+3) design was used to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) to select the Recommended Phase 2 Dose (RP2D) of ORIC-101 in combination with enzalutamide in patients with metastatic CRPC progressing on enzalutamide 160 mg, dosed once daily (NCT04033328). ORIC-101, at doses ranging from 80 to 240 mg once daily, given in a continuous dosing regimen, was added to enzalutamide at the time of disease progression. Plasma PK and PD biomarkers were assessed on multiple days and times before and after dosing. PD modulation in blood-derived peripheral blood mononuclear cells (PBMCs) was assessed by RT-qPCR for GR target genes. Antitumor activity was assessed by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) and RECIST 1.1. Results: 10 patients were treated in 3 cohorts in the dose escalation portion of the study. ORIC-101 exposure increased with dose and no drug-drug interaction (DDI) was observed that necessitated reduction from the standard enzalutamide dose of 160 mg. No dose limiting toxicities were observed at any dose level. Based upon plasma exposure and PD modulation, the RP2D was established as 240 mg ORIC-101 plus 160 mg enzalutamide, both dosed once daily continuously in 28-day cycles. All adverse events (AEs) were Grade 1 or 2 with the most common ( & gt;15%), treatment-related AEs being fatigue (40%), nausea (30%), constipation (20%), decreased appetite (20%), high aspartate aminotransferase (20%), high alkaline phosphatase (20%), and headache (20%). There were no Grade ≥3 treatment-related AEs. Biomarker data demonstrated ORIC-101 induced reduction in GR target gene expression in PBMCs, indicating PD modulation across dose levels of ORIC-101. Data will be updated at the time of the presentation. Conclusions: Preliminary evidence suggests that ORIC-101 effectively modulates GR and has an acceptable tolerability profile when combined with enzalutamide. Dose expansion is ongoing at the RP2D. Citation Format: Wassim Abida, Neeraj Agarwal, Andrew W. Hahn, Neal Shore, Paul Sieber, Tanya Dorff, Mathew Rettig, Mathew Smith, Paul Monk, Rongda Xu, Ann Johnson, Anneleen Daemen, Edna Chow Maneval, Pratik S. Multani, Rupal Patel, Michael J. Morris. Initial results from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide in patients with metastatic prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P041.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-21-P041
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
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    Interleukin 33 Signaling Restrains Sporadic Colon Cancer in an Interferon-γ–Dependent Manner
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Immunology Research Vol. 6, No. 4 ( 2018-04-01), p. 409-421
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 6, No. 4 ( 2018-04-01), p. 409-421
    Abstract: Interleukin 33 (IL33) is an inflammatory cytokine released during necrotic cell death. The epithelium and stroma of the intestine express large amounts of IL33 and its receptor St2. IL33 is therefore continuously released during homeostatic turnover of the intestinal mucosa. Although IL33 can prevent colon cancer associated with inflammatory colitis, the contribution of IL33 signaling to sporadic colon cancer remains unknown. Here, we utilized a mouse model of sporadic colon cancer to investigate the contribution of IL33 signaling to tumorigenesis in the absence of preexisting inflammation. We demonstrated that genetic ablation of St2 enhanced colon tumor development. Conversely, administration of recombinant IL33 reduced growth of colon cancer cell allografts. In reciprocal bone marrow chimeras, the concurrent loss of IL33 signaling within radioresistant nonhematopoietic, and the radiosensitive hematopoietic, compartments was associated with increased tumor burden. We detected St2 expression within the radioresistant mesenchymal cell compartment of the colon whose stimulation with IL33 induced expression of bona fide NF-κB target genes. Mechanistically, we discovered that St2 deficiency within the nonhematopoietic compartment coincided with increased abundance of regulatory T cells and suppression of an IFNγ gene expression signature, whereas IL33 administration triggered IFNγ expression by tumor allograft-infiltrating T cells. The decrease of this IFNγ gene expression signature was associated with more aggressive disease in human colon cancer patients, suggesting that lack of IL33 signaling impaired the generation of a potent IFNγ-mediated antitumor immune response. Collectively, our data reveal that IL33 functions as a tumor suppressor in sporadic colon cancer. Cancer Immunol Res; 6(4); 409–21. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-17-0218
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
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    Germline Variants and Advanced Colorectal Adenomas: Adenoma Prevention with Celecoxib Trial Genome-wide Association Study
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 23 ( 2013-12-01), p. 6430-6437
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 23 ( 2013-12-01), p. 6430-6437
    Abstract: Purpose: Identification of single-nucleotide polymorphisms (SNP) associated with development of advanced colorectal adenomas. Experimental Design: Discovery phase: 1,406 Caucasian patients (139 advanced adenoma cases and 1,267 controls) from the Adenoma Prevention with Celecoxib (APC) trial were included in a genome-wide association study (GWAS) to identify variants associated with postpolypectomy disease recurrence. Genome-wide significance was defined as false discovery rate less than 0.05, unadjusted P = 7.4 × 10−7. Validation phase: results were further evaluated using 4,175 familial colorectal adenoma cases and 5,036 controls from patients of European ancestry [COloRectal Gene Identification consortium (CORGI), Scotland, Australia, and VQ58]. Results: Our study identified eight SNPs associated with advanced-adenoma risk in the APC trial (rs2837156, rs7278863, rs2837237, rs2837241, rs2837254, rs741864 at 21q22.2, and rs1381392 and rs17651822 at 3p24.1, at P & lt; 10−7 level with OR & gt; 2). Five variants in strong pairwise linkage disequilibrium (rs7278863, rs2837237, rs741864, rs741864, and rs2837241; r2 = 0.8–1) are in or near the coding region for the tight junction adhesion protein, IGSF5. An additional variant associated with advanced adenomas, rs1535989 [minor allele frequency, 0.11; OR, 2.09; 95% confidence interval (CI), 1.50–2.91], also predicted colorectal cancer development in a validation analysis (P = 0.019) using a series of adenoma cases or colorectal cancer (CORGI study) and 3 sets of colorectal cancer cases and controls (Scotland, VQ58, and Australia; N = 9,211). Conclusions: Our results suggest that common polymorphisms contribute to the risk of developing advanced adenomas and might also contribute to the risk of developing colorectal cancer. The variant at rs1535989 may identify patients whose risk for neoplasia warrants increased colonoscopic surveillance. Clin Cancer Res; 19(23); 6430–7. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-0550
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 4
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    Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 11 ( 2022-06-01), p. 2237-2247
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 11 ( 2022-06-01), p. 2237-2247
    Abstract: To report efficacy and safety of samotolisib (LY3023414; PI3K/mTOR dual kinase and DNA-dependent protein kinase inhibitor) plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) following cancer progression on abiraterone. Patients and Methods: In this double-blind, placebo-controlled phase Ib/II study (NCT02407054), following a lead-in segment for evaluating safety and pharmacokinetics of samotolisib and enzalutamide combination, patients with advanced castration-resistant prostate cancer with progression on prior abiraterone were randomized to receive enzalutamide (160 mg daily)/samotolisib (200 mg twice daily) or placebo. Primary endpoint was progression-free survival (PFS) assessed by Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Secondary and exploratory endpoints included radiographic PFS (rPFS) and biomarkers, respectively. Log-rank tests assessed treatment group differences. Results: Overall, 13 and 129 patients were enrolled in phase Ib and II, respectively. Dose-limiting toxicity was not reported in patients during phase Ib and mean samotolisib exposures remained in the targeted range despite a 35% decrease when administered with enzalutamide. In phase II, median PCWG2-PFS and rPFS was significantly longer in the samotolisib/enzalutamide versus placebo/enzalutamide arm (3.8 vs. 2.8 months; P = 0.003 and 10.2 vs. 5.5 months; P = 0.03), respectively. Patients without androgen receptor splice variant 7 showed a significant and clinically meaningful rPFS benefit in the samotolisib/enzalutamide versus placebo/enzalutamide arm (13.2 months vs. 5.3 months; P = 0.03). Conclusions: Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone, and this may be enriched in patients with PTEN intact and no androgen receptor splice variant 7.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-2326
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
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    Abstract 2729: Development of a targeted liquid biopsy for early gynecologic cancer detection leads to discovery of a highly prevalent genomic landscape of cancer driver gene mutations in uterine tissue from women without cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2729-2729
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2729-2729
    Abstract: Introduction: Ovarian and endometrial cancers are, respectively, the most lethal and most frequent female reproductive tract malignancies. Currently, there are no effective screening methodologies or protocols for these cancers. We hypothesized that the use of ultra-deep, targeted gene sequencing on a highly specific and gynecologic cancer-focused analyte source, namely, uterine lavage fluid, could detect somatic mutations associated with these cancers. Using these highly sensitive NGS-based assays, we demonstrated both (1) the ability to detect tumor-specific mutations in uterine lavage from women even with microscopic stage IA ovarian and endometrial cancers and (2) the existence of highly prevalent populations of cancer driver gene mutated cells in uterine tissue from women without cancer. Methods: In total, and following written informed consent, samples were prospectively collected and analyzed from two institutions from more than 250 women at the time of their surgery. Sequencing was performed using both Ion Torrent and Illumina-based sequencing and additional orthogonal mutation validation was performed using dPCR and Sanger sequencing. Results: Targeted sequencing of cellular and cell free DNA isolated from uterine lavage samples was performed on all samples in a blinded fashion. Histopathologic diagnosis and sample decoding, revealed that lavage mutations were present in nearly all women with ovarian and endometrial cancer, even those with microscopic stage IA disease. These mutations were demonstrated to be tumor-specific by sequencing their respective tumors. Notably, we also identified mutations in approximately half of all women without any evidence of cancer. To define the possible origin of these mutations in normal tissue, we analyzed uterine tissue from women without cancer. Two hundred biopsy samples were obtained from 24 uterine samples following hysterectomy for non-cancerous conditions. Remarkably, sequencing revealed relatively high allele fraction cancer-associated mutations in more than half of these samples. The overwhelming majority of samples harbored low frequency mutations. Conclusions: Our studies demonstrate the ability to detect with very high sensitivity, tumor-specific somatic mutations in women with ovarian and endometrial cancers; suggesting the future possibility of earlier diagnosis and better outcomes. At the same time, our studies again highlight caveats regarding NGS-based results for cancer screening. Finally, the identification of a previously unknown, highly prevalent, cancer-driver mutation landscape in apparently normal uterine tissue opens the door onto new areas of biologic exploration for understanding tumorigenesis and the protective mechanisms which inhibit cancer development. Citation Format: Deep S. Pandya, Shannon Tomita, Olga Camacho, Sabina Swierczek, Catalina Camacho, Kelsey Engelman, Stephanie Polukort, Maria Mercedes Padron, Jordan RoseFigura, Jon Irish, Linus Chuang, Vaagn Andikyan, Samantha Cohen, Paul Fiedler, Steven Sieber, Ie-Ming Shih, Jean-Noel Billaud, Boris Reva, Robert Sebra, Peter Dottino, John A. Martignetti. Development of a targeted liquid biopsy for early gynecologic cancer detection leads to discovery of a highly prevalent genomic landscape of cancer driver gene mutations in uterine tissue from women without cancer [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 2729.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2729
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 6
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    KRAS Mutation Is Associated with Lung Metastasis in Patients with Curatively Resected Colorectal Cancer
    American Association for Cancer Research (AACR) ; 2011
    In:  Clinical Cancer Research Vol. 17, No. 5 ( 2011-03-01), p. 1122-1130
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 5 ( 2011-03-01), p. 1122-1130
    Abstract: Purpose: Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse. Experimental Design: One hundred colorectal cancer metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analyzed for genes with identified mutations. Mutation prevalence was compared between (a) metastases from liver (n = 65), lung (n = 50), and brain (n = 46), (b) metastases and matched primary cancers, and (c) metastases and an independent cohort of primary cancers (n = 604). Mutations differing between metastasis sites were evaluated as markers for site of relapse in 859 patients from the VICTOR trial. Results: In colorectal cancer metastases, mutations were detected in 4 of 19 oncogenes: BRAF (3.1%), KRAS (48.4%), NRAS (6.2%), and PIK3CA (16.1%). KRAS mutation prevalence was significantly higher in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P = 0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. Compared with independent primary cancers, KRAS mutations were more common in lung and brain metastases (P & lt; 0.005), but similar in liver metastases. Correspondingly, KRAS mutation was associated with lung relapse (HR = 2.1; 95% CI, 1.2 to 3.5, P = 0.007) but not liver relapse in patients from the VICTOR trial. Conclusions: KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients. Our data highlight the potential of somatic mutations for informing surveillance strategies. Clin Cancer Res; 17(5); 1122–30. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-10-1720
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 7
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    Abstract 3994: Herpes virus microRNA expression and significance in serous ovarian cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3994-3994
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3994-3994
    Abstract: Serous ovarian cancer (SEOC) is the deadliest gynecologic malignancy. MicroRNAs (miRNAs) are a class of small noncoding RNAs which regulate gene expression and protein translation. MiRNAs are also encoded by viruses with the intent of regulating their own genes and those of the infected cells. This is the first study assessing viral miRNAs in SEOC. MiRNAs sequencing data from 487 SEOC patients were downloaded from the TCGA website and analyzed through in-house sequencing pipeline. To cross-validate TCGA analysis, we measured the expression of miR-H25 by quantitative immunofluorescence in an additional cohort of 161 SEOC patients. Gene, miRNA expression, and cytotoxicity assay were performed on multiple ovarian cancer cell lines transfected with miR-H25 and miR-BART7. Outcome analysis was performed using multivariate Cox and Kaplan-Meier method. Viral miRNAs are more expressed in SEOC than in normal tissues. Moreover, Herpetic viral miRNAs (miR-BART7 from EBV and miR-H25 from HSV-2) are significant and predictive biomarkers of outcome in multivariate Cox analysis. MiR-BART7 correlates with resistance to first line chemotherapy and early death, whereas miR-H25 appears to impart a protective effect and long term survival. Integrated analysis of gene and viral miRNAs expression suggests that miR-BART7 induces directly cisplatin-resistance, while miR-H25 alters RNA processing and affects the expression of noxious human miRNAs such as miR-143. This is the first investigation linking viral miRNA expression to ovarian cancer outcome. Viral miRNAs can be useful to develop biomarkers for early diagnosis and as a potential therapeutic tool to reduce SEOC lethality. Citation Format: Deep Pandya, Marisa Mariani, Mark McHugh, Mirko Andreoli, Steven Sieber, Shiquan He, Candice Dowell-Martino, Paul Fiedler, Giovanni Scambia, Cristiano Ferlini. Herpes virus microRNA expression and significance in serous ovarian cancer. [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 3994. doi:10.1158/1538-7445.AM2015-3994
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-3994
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 8
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    Abstract 916: A multidimensional analysis of predictive biomarkers in colorectal cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 916-916
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 916-916
    Abstract: Background: CRC cancer is one of the deadliest diseases in Western countries. In order to develop predictive biomarkers for CRC (colorectal cancer) aggressiveness, we analyzed retrospectively 267 CRC patients via a novel, multidimensional biomarker platform. Methods: Using nanofluidic technology for qPCR analysis and quantitative fluorescent immunohistochemistry for protein analysis, we assessed 33 microRNAs, 124 mRNAs and 9 protein antigens. Analysis was conducted in each single dimension (microRNA, gene or protein) using both the multivariate Cox model and Kaplan-Meier method. Thereafter, we simplified the censored survival data into binary response data (aggressive vs. non aggressive cancer). Subsequently, we combined the data into multidimensional scores using inverse sliced regression for sufficient dimension reduction. Accuracy was assessed using the Area under the Curve (AUC) and the receiver operating characteristic (ROC) method. Results: Single dimension analysis led to the discovery of individual factors that were significant predictors of outcome. These included seven specific microRNAs, four genes, and one protein. When these factors were quantified individually as predictors of aggressive disease, the highest demonstrable area under the curve (AUC) was 0.68. By contrast, when all results from single dimensions were combined into multidimensional biomarkers, AUCs were dramatically increased with values approaching and even exceeding 0.9. Conclusions: Single dimension analysis generates statistically significant predictors, but their predictive strengths are suboptimal for clinical utility. A novel, multidimensional approach overcomes these deficiencies. Newly derived multidimensional biomarkers have the potential to meaningfully guide the selection of therapeutic agents for individual patients while elucidating molecular mechanisms driving disease progression. Citation Format: Marisa Mariani, Shiquan He, Mark McHugh, Mirko Andreoli, Deep Pandya, Steven Sieber, Zheyang Wu, Paul Fiedler, Shohreh Shahabi, Cristiano Ferlini. A multidimensional analysis of predictive biomarkers in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 916. doi:10.1158/1538-7445.AM2014-916
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-916
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 9
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    Abstract LB-B23: Medulloblastoma regulatory circuitries reveal subgroup-specific cellular origins
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. LB-B23-LB-B23
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. LB-B23-LB-B23
    Abstract: Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is currently lacking. Using H3K27ac and BRD4 ChIP-Seq, coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors responsible for subgroup divergence that validated by ChIP-Seq and implicated candidate cells-of-origin for Group 4. Our integrated analysis of cis-regulatory elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins. Citation Format: Charles Y. Lin, Serap Erkek, Yiai Tong, Linlin Yang, Alexander J. Federation, Marc Zapatka, Parthiv Haldipur, Daisuke Kawauchi, Thomas Risch, Hans-Jörg Warnatz, Barbara Worst, Bensheng Ju, Brent A. Orr, Rhamy Zeid, Donald R. Polaski, Maia Segura-Wang, Sebastian M. Waszak, David TW Jones, Marcel Kool, Volker Hovestadt, Ivo Buchhalter, Laura Sieber, Pascal Johann, Stefan Gröschel, Marina Ryzhova, Andrey Korshunov, Wenbiao Chen, Victor V. Chizhikov, Kathleen J. Millen, Vyacheslav Amstislavskiy, Hans Lehrach, Marie-Laure Yaspo, Roland Eils, Peter Lichter, Jan O. Korbel, Stefan Pfister, James E. Bradner, Paul A. Northcott. Medulloblastoma regulatory circuitries reveal subgroup-specific cellular origins. [abstract] . In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B23.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-LB-B23
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 10
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    Abstract 3725: HGF/c-Met axis drives cancer aggressiveness in the neo-adjuvant setting of ovarian cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3725-3725
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3725-3725
    Abstract: Background: Ovarian cancer is the most lethal gynecologic malignancy. Recently, NACT has been clinically tested as alternative approach for the management of ovarian cancer patients. A biological predictor helpful in selecting patients for NACT would be desirable. Indeed, chemotherapy has a strong impact in modifying the biology of tumor and rendering it more aggressive. This study was aimed at identifying actionable mechanisms of resistance to NACT. Methods: Expression of a panel of microRNAs was screened in a discovery set of 85 patients. Analysis of the potential targets was conducted in the same RNAs by calculating significant correlations between microRNAs and genes. Quantitative fluorescent immunohistochemistry was employed in a validation set of 109 patients. Pre and post-NACT specimens were analyzed in multiple cores of tumor from formalin fixed paraffin embedded material (FFPE). Results: MiR-193a-5p was significantly overexpressed in the NACT setting. Analysis of its potential targets demonstrated that this microRNA is also significantly correlated with the expression levels of HGF and MET genes. Analysis of protein expression in samples taken before and after NACT demonstrated that both HGF and c-Met are increased after NACT. Patients who relapse shortly after NACT exhibited the highest relative basal expression of both HGF and c-Met, while the opposite phenomenon was observed in the best responders. Conclusion: These findings demonstrate that NACT refractory patients express activation of the HGF/c-Met pathway. HGF/c-Met expression may help select eligible patients for this modality of treatment. Moreover, inhibitors of this pathway may improve the efficacy of NACT. Citation Format: Marisa Mariani, Mark McHugh, Marco Petrillo, Steven Sieber, Shiquan He, Mirko Andreoli, Paul Fiedler, Giovanni Scambia, Shohreh Shahabi, Cristiano Ferlini. HGF/c-Met axis drives cancer aggressiveness in the neo-adjuvant setting of ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3725. doi:10.1158/1538-7445.AM2014-3725
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-3725
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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