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Sökning: WFRF:(Hegardt Cecilia)

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1.
  • Borgström, Björn, et al. (författare)
  • Structure–Activity Relationships in Salinomycin : Cytotoxicity and Phenotype Selectivity of Semi-synthetic Derivatives
  • 2017
  • Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539. ; 23:9, s. 2077-2083
  • Tidskriftsartikel (refereegranskat)abstract
    • The ionophore salinomycin has attracted attention for its exceptional ability to selectively reduce the proportion of cells with stem-like properties in cancer cell populations of varying origin. Targeting the tumorigenicity of such cells is of interest as they are implicated in recurrence, metastasis, and drug resistance. Structural derivatives of salinomycin are thus sought after, both as tools for probing the molecular mechanism(s) underlying the observed phenotype effects, and for improving selectivity and activity against cancer stem cells. Synthetic strategies for modification of each of the directly accessible functional groups of salinomycin are presented and the resulting library of analogues was investigated to establish structure–activity relationships, both with respect to cytotoxicity and phenotype selectivity in breast cancer cells. 20-O-Acylated derivatives stand out by exhibiting both improved selectivity and activity. Mechanistically, the importance of the ionophore properties of salinomycin is highlighted by a significant loss of activity by modifications directly interfering with either of the two primary ion coordinating motifs in salinomycin, the C11 ketone and the C1 carboxylate.
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2.
  • Borgström, Björn, et al. (författare)
  • Synthetic modification of salinomycin: selective O-acylation and biological evaluation
  • 2013
  • Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1364-548X .- 1359-7345. ; 49:85, s. 9944-9946
  • Tidskriftsartikel (refereegranskat)abstract
    • Salinomycin has found renewed interest as an agent for prevention of cancer recurrence through selectively targeting cancer stem cells. Strategies for generation of improved salinomycin analogs by individual modification of its hydroxyl groups are presented. An evaluation of the dose-response effects of the resulting library on breast cancer cell lines shows that acylation of the C20 hydroxyl can be used to improve IC50 values down to one fifth that of salinomycin.
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3.
  • Brueffer, Christian, et al. (författare)
  • Abstract P4-09-03: On the development and clinical value of RNA-sequencing-based classifiers for prediction of the five conventional breast cancer biomarkers: A report from the population-based multicenter SCAN-B study
  • 2018
  • Ingår i: Cancer research. Supplement. - 1538-7445. ; 78:4
  • Konferensbidrag (refereegranskat)abstract
    • Background:In early breast cancer, five histopathological biomarkers are part of current clinical routines and used for determining prognosis and treatment: estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (ERBB2/HER2), Ki67, and Nottingham histological grade (NHG). We aimed to develop classifiers for these biomarkers based on tumor mRNA-sequencing (RNA-seq), compare classification performance to conventional histopathology, and test whether RNA-seq-based predictors could add value for patient risk-stratification.Patients and Methods:In total, 3678 breast tumors were studied. For 405 breast tumors in the training cohort, a comprehensive histopathological biomarker evaluation was performed by three pathology readings to estimate inter-pathologist variability on the original diagnostic slides as well as on repeat immunostains for this study, and the consensus biomarker status for all five conventional biomarkers was determined. Whole transcriptome gene expression profiling was performed by RNA-sequencing on the Illumina platform. Using RNA-seq-derived tumor gene expression data as input, single-gene classifiers (SGC) and multi-gene classifiers (MGC) were trained on the consensus pathology biomarker labels. The trained classifiers were tested on an independent prospective population-based series of 3273 primary breast cancer cases from the multicenter SCAN-B study with median 41 months follow-up (ClinicalTrials.gov identifier NCT02306096), and classifications were evaluated by agreement statistics and by Kaplan-Meier and Cox regression survival analyses.Results:For the histopathological evaluation, pathologist evaluation concordance was high for ER, PgR, and HER2 (average kappa values of .920, .891, and .899, respectively), but moderate for Ki67 and NHG (.734 and .581). Classification concordance between RNA-seq classifiers and histopathology for the independent 3273-cohort was similar to that within histopathology assessments, with SGCs slightly outperforming MGCs. Importantly, patients with discordant results, classified as hormone responsive (HoR+) by histopathology but non-hormone responsive by MGC, presented with significantly inferior overall survival compared to patients with concordant results. These results extended to patients with no adjuvant systemic therapy (hazard ratio, HR, 4.54; 95% confidence interval, CI, 1.42-14.5), endocrine therapy alone (HR 3.46; 95% CI, 2.01-5.95), or receiving chemotherapy (HR 2.57; 95% CI 1.13-5.86). For HoR+ cases receiving endocrine therapy alone, the MGC HoR classifier remained significant after multivariable adjustment (HR 3.14; 95% CI, 1.75-5.65).Conclusions:RNA-seq-based classifiers for the five key early breast cancer biomarkers were generally equivalent to conventional histopathology with regards to classification error rate. However, when benchmarked using overall survival, our RNA-seq classifiers provided added clinical value in particular for cases that are determined by histopathology to be hormone-responsive but by RNA-seq appear hormone-insensitive and have a significantly poorer outcome when treated with endocrine therapy alone
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4.
  • Brueffer, Christian, et al. (författare)
  • Clinical Value of RNA Sequencing–Based Classifiers for Prediction of the Five Conventional Breast Cancer Biomarkers: A Report From the Population-Based Multicenter Sweden Cancerome Analysis Network—Breast Initiative
  • 2018
  • Ingår i: JCO Precision Oncology. - 2473-4284. ; 2, s. 1-18
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeIn early breast cancer (BC), five conventional biomarkers—estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki67, and Nottingham histologic grade (NHG)—are used to determine prognosis and treatment. We aimed to develop classifiers for these biomarkers that were based on tumor mRNA sequencing (RNA-seq), compare classification performance, and test whether such predictors could add value for risk stratification.MethodsIn total, 3,678 patients with BC were studied. For 405 tumors, a comprehensive multi-rater histopathologic evaluation was performed. Using RNA-seq data, single-gene classifiers and multigene classifiers (MGCs) were trained on consensus histopathology labels. Trained classifiers were tested on a prospective population-based series of 3,273 BCs that included a median follow-up of 52 months (Sweden Cancerome Analysis Network—Breast [SCAN-B], ClinicalTrials.gov identifier: NCT02306096), and results were evaluated by agreement statistics and Kaplan-Meier and Cox survival analyses.ResultsPathologist concordance was high for ER, PgR, and HER2 (average κ, 0.920, 0.891, and 0.899, respectively) but moderate for Ki67 and NHG (average κ, 0.734 and 0.581). Concordance between RNA-seq classifiers and histopathology for the independent cohort of 3,273 was similar to interpathologist concordance. Patients with discordant classifications, predicted as hormone responsive by histopathology but non–hormone responsive by MGC, had significantly inferior overall survival compared with patients who had concordant results. This extended to patients who received no adjuvant therapy (hazard ratio [HR], 3.19; 95% CI, 1.19 to 8.57), or endocrine therapy alone (HR, 2.64; 95% CI, 1.55 to 4.51). For cases identified as hormone responsive by histopathology and who received endocrine therapy alone, the MGC hormone-responsive classifier remained significant after multivariable adjustment (HR, 2.45; 95% CI, 1.39 to 4.34).ConclusionClassification error rates for RNA-seq–based classifiers for the five key BC biomarkers generally were equivalent to conventional histopathology. However, RNA-seq classifiers provided added clinical value in particular for tumors determined by histopathology to be hormone responsive but by RNA-seq to be hormone insensitive.
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6.
  • Brueffer, Christian, et al. (författare)
  • The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome
  • 2020
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Breast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. Within the Sweden Cancerome Analysis Network–Breast project (SCAN-B; ClinicalTrials.govNCT02306096), an ongoing study elucidating the tumor transcriptomic profiles for thousands of breast cancers prospectively, we developed an optimized pipeline for detection of single nucleotide variants and small insertions and deletions from RNA sequencing (RNA-seq) data, and profiled a large real-world population-based cohort of 3,217 breast tumors. We use it to describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population-based cohort of patients, and relate it to patient overall survival. We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such asPIK3CA,TP53, andERBB2, as well as the status of key molecular pathways and tumor mutational burden, and identify potentially druggable genes in 86.8% percent of tumors. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source web-based application, the SCAN-B MutationExplorer, accessible athttp://oncogenomics.bmc.lu.se/MutationExplorer. These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling.
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7.
  • Brueffer, Christian, et al. (författare)
  • The mutational landscape of the SCAN‐B real‐world primary breast cancer transcriptome
  • 2020
  • Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 12:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast cancer is a disease of genomic alterations, of which the panorama of somatic mutations and how these relate to subtypes and therapy response is incompletely understood. Within SCAN‐B (ClinicalTrials.gov: NCT02306096), a prospective study elucidating the transcriptomic profiles for thousands of breast cancers, we developed a RNA‐seq pipeline for detection of SNVs/indels and profiled a real‐world cohort of 3,217 breast tumors. We describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population‐based cohort and relate it to patient survival. We demonstrate that RNA‐seq can be used to call mutations in genes such as PIK3CA, TP53, and ERBB2, as well as the status of molecular pathways and mutational burden, and identify potentially druggable mutations in 86.8% of tumors. To make this rich dataset available for the research community, we developed an open source web application, the SCAN‐B MutationExplorer (http://oncogenomics.bmc.lu.se/MutationExplorer). These results add another dimension to the use of RNA‐seq as a clinical tool, where both gene expression‐ and mutation‐based biomarkers can be interrogated in real‐time within 1 week of tumor sampling.
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8.
  • Cirenajwis, Helena, et al. (författare)
  • Reduction of the putative CD44+CD24- breast cancer stem cell population by targeting the polyamine metabolic pathway with PG11047.
  • 2010
  • Ingår i: Anti-Cancer Drugs. - 0959-4973. ; 21:10, s. 897-906
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer stem cells (CSCs) are considered to be of particular concern in cancer as they possess inherent properties of self-renewal and differentiation, along with expressing certain genes related to a mesenchymal phenotype. These features favour the promotion of tumour recurrence and metastasis in cancer patients. Thus, the optimal chemotherapeutic treatment should target the CSC population, either by killing these cells and/or by inducing their transition to a more differentiated epithelial-like phenotype. Experiments were carried out on the trastuzumab-resistant human epidermal growth factor receptor 2-overexpressing breast cancer cell line JIMT-1 to unravel the chemotherapeutic effects of the polyamine analogue [N,N]bis(ethyl)-cis-6,7-dehydrospermine (PG11047) and of the polyamine biosynthetic inhibitor 2-difluoromethylornithine (DFMO) on the CD44CD24 CSC population. Furthermore, effects on the properties of self-renewal and epithelial/mesenchymal markers were also investigated. Treatment with PG11047 reduced the CD44CD24 subpopulation of JIMT-1 cells by approximately 50%, inhibited and/or reduced self-renewal capability of the CSC population, decreased cell motility and induced expression of mesenchymal to epithelial transition-associated proteins that are involved in promoting an epithelial phenotype. By contrast, DFMO slightly increased the CD44CD24 subpopulation, increased cell motility and the level of mesenchymal-related proteins. DFMO treatment reduced the self-renewal capability of the CSC population. Both PG11047 and DFMO reduced the expression of the human epidermal growth factor receptor 2 protein, which is correlated to malignancy and resistance to trastuzumab in JIMT-1 cells. Our findings indicate that treatment with PG11047 targeted the CSC population by interfering with several stem cell-related properties, such as self-renewal, differentiation, motility and the mesenchymal phenotype.
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10.
  • Dahlgren, Malin, et al. (författare)
  • Preexisting Somatic Mutations of Estrogen Receptor Alpha (ESR1) in Early-Stage Primary Breast Cancer
  • 2021
  • Ingår i: JNCI Cancer Spectrum. - : Oxford University Press (OUP). - 2515-5091. ; 5:2
  • Tidskriftsartikel (refereegranskat)abstract
    • More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1), the most important factor for directing anti-estrogenic endocrine therapy (ET). Recently, mutations in ESR1 were identified as acquired mechanisms of resistance to ET, found in 12% to 55% of metastatic breast cancers treated previously with ET. We analyzed 3217 population-based invasive primary (nonmetastatic) breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096), sampled from initial diagnosis prior to any treatment, for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by droplet digital polymerase chain reaction on tumor and normal DNA. Patient outcomes were analyzed using Kaplan-Meier estimation and a series of 2-factor Cox regression multivariable analyses. We identified ESR1 resistance mutations in 30 tumors (0.9%), of which 29 were ER positive (1.1%). In ET-treated disease, presence of ESR1 mutation was associated with poor relapse-free survival and overall survival (2-sided log-rank test P < .001 and P = .008, respectively), with hazard ratios of 3.00 (95% confidence interval = 1.56 to 5.88) and 2.51 (95% confidence interval = 1.24 to 5.07), respectively, which remained statistically significant when adjusted for other prognostic factors. These population-based results indicate that ESR1 mutations at diagnosis of primary breast cancer occur in about 1% of women and identify for the first time in the adjuvant setting that such preexisting mutations are associated to eventual resistance to standard hormone therapy. If replicated, tumor ESR1 screening should be considered in ER-positive primary breast cancer, and for patients with mutated disease, ER degraders such as fulvestrant or other therapeutic options may be considered as more appropriate.
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