GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Abstract C075: The use of 4HF Cancer Data Miner platform for an in Silico pharmacogenomic study predicting tumor response to the CDK4/6 inhibitor Palbociclib
    American Association for Cancer Research (AACR) ; 2019
    In:  Molecular Cancer Therapeutics Vol. 18, No. 12_Supplement ( 2019-12-01), p. C075-C075
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 18, No. 12_Supplement ( 2019-12-01), p. C075-C075
    Abstract: 4HF Biotec recently developed an in-silico platform dedicated to cancer data investigations. It connects cancer-related molecular and drug sensitivity information enabling target and biomarker discovery. We used the platform to perform an integrative pharmacogenomic study for the CDK4/6 inhibitor Palbociclib. CDK4/6 inhibitors are molecules blocking E2F1 mediated G1/S cell cycle progression. Palbociclib is already approved in the clinic for treatment of HR-positive, ERBB2 negative advanced and metastatic breast cancer. Clinical trials in other tumor types such as leukemia, head and neck, ovarian and non-small cell lung cancer are also ongoing. In this context, large preclinical studies may help for identification of companion diagnostics improving patient selection. In a data-driven approach, we searched for molecular events associated with cancer response and resistance to Palbociclib. A publicly available dataset was used that contains 843 tumor cell lines which were tested for response to Palbociclib in a 2D monolayer assay in vitro (GDSC). Palbociclib IC50s values were integrated to our platform and were evaluated for associations with the molecular features of the cell lines including mutated genes (whole exome sequencing), gene deletions or amplifications (SNP6.0 microarrays) and gene expression (Affymetrix HGU133 plus 2.0) or combinations. The resulting biomarker candidates were analyzed for predictivity in an independent dataset of 142 tumor cell lines obtained from 4HF Biotec (internal data). In vitro, the best efficacies were observed in cell lines from hematological cancers (leukemia and lymphoma) and solid tumors such as renal, neuroblastoma, head and neck cancers. Very sensitive cell lines were also seen in most of the other tumor types tested. Surprisingly, the panel of breast cancer cell lines was among those with the lowest proportion of sensitive cell lines (6 out of 43) with those derived from small cell lung and uterus cancers. Statistical analyses identified alterations in RB1 gene by far the most prominent biomarker associated with resistance to Palbociclib (adjusted p value 2.53.10-9) and that can occur by gene deletions, mutations or loss of expression. Other genomic alterations such as the loss of chromosome 9 containing CDKN2A and CDKN2B were associated with increased response rates. In contrast, cell lines with chromosome amplification in 17q containing ERBB2 or chromosome 1 containing MYCL were mainly resistant to the compound (p & lt;0.05). At the gene expression level, CDK6 and RB1 were among the most significant markers of sensitivity. Focusing on cell lines not altered for RB1, pathway analysis revealed additionally that the genes of the mesenchymal or poorly differentiated phenotypes were the strongest predictors of response. The present pharmacogenomic study allowed identification of a relevant panel of biomarkers predicting Palbociclib response or resistance. Their validation should continue for clinical use in different tumor types and a predictive algorithm could be constructed to improve identification of candidate cancer patients for such treatment. We believe such approach should be more systematically done in programs of drug development. Citation Format: Vincent Vuaroqueaux, Hoor Al Hasani, Gerhard Kelter, Hans R Hendriks, Heinz-Herbert Fiebig. The use of 4HF Cancer Data Miner platform for an in Silico pharmacogenomic study predicting tumor response to the CDK4/6 inhibitor Palbociclib [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C075. doi:10.1158/1535-7163.TARG-19-C075
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-19-C075
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 1027: ProLiFiler and Cancer Data Miner, combined platforms for preclinical investigation to scrutinize impact of inhibitors on the KRAS, PI3K and MDM2 signaling pathways
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1027-1027
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1027-1027
    Abstract: Testing novel anti-cancer agents across large panel of tumor models covering genetic diversity of cancers is increasingly considered as a cornerstone of preclinical development. For this purpose, Reaction Biology developed “ProLiFiler” a standard panel of 140 cell lines (CLs) covering most common cancer types to evaluate anti-proliferative activity of novel drugs. Partnering has been made with 4HF Biotec and their in-silico platform, named “Cancer Data Miner”, to investigate and to understand molecular basis of drug sensitivity. Here we report the use of our platforms to realize integrative pharmacogenomic studies for three recent small molecules targeting major altered pathways in cancers. It includes SOS1::KRAS interaction inhibitor BI-3406, MDM2 inhibitor Nutlin-3a, and PI3K inhibitor Taselisib. Main goal of the study is to provide meaningful information for these three drugs regarding their efficacy and potency, the validation of their mechanism of actions (MOA), the suitable clinical indications, possible drug combinations and the predictive biomarkers of sensitivity or resistance. The three compounds are tested for anti-proliferative activity in vitro in a 2D monolayer assay using the “ProLiFiler”CLs panel. For data analytics, the resulting in vitro data are loaded on the “Cancer Data Miner” platform and connected to CL annotations including whole exome mutations, chromosomal aberrations, gene expression profiles or drug sensitivity profiles. The drug response profiles will be reported for the three compounds individually and compare between them, showing respective efficacy, potency, and CL/cancer entity selectivity. Using the MOA Finder tool, we will correlate BI-3406, Nutlin-3a, and Taselisib individual IC50 profiles to those of more than 800 compounds with known MOA that are integrated on the platform. The analyses will show the drugs most closely related to the 3 compounds and that are expected to have similar MOA. With the biomarker discovery tools, we will run high throughput statistical analyses to reveal whole exome mutations, copy number variations and expression significantly associated with drug sensitivity/resistance. For interpretation, pathway and enrichment analysis will be presented. A focus will be made on key alterations like KRAS and MAPK related genes, TP53-MDM2 and PIK3CA-PTEN to evaluate their predictivity. The work will be also completed by functional analysis, for instance, by assessing the effect of BI-3406 on ERK-MEK activation, and the impact of MDM2 inhibition on apoptotic markers. The present work will show the whole panel of analyses proposed by 140 CL-ProLiFiler and Cancer Data Miner complementary platforms, allowing to acquire key information at an early stage of drug development and helping to setup next steps such as selection of models for in vivo testing. Citation Format: Vincent Vuaroqueaux, Daniel Feger, Hoor Al-Hasani, Oliver Siedentopf, Anne-Lise Peille, Sarah Ulrich, Sebastian Dempe, Heinz-Herbert Fiebig, Jan Erik Ehlert. ProLiFiler and Cancer Data Miner, combined platforms for preclinical investigation to scrutinize impact of inhibitors on the KRAS, PI3K and MDM2 signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1027.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1027
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Abstract 2196: Strong anti-tumor activity of MEK inhibitor GDC-0623 and determination of predictive biomarkers
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2196-2196
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2196-2196
    Abstract: MEK inhibitors emerged as a promising class of anti-cancer agents to inhibit KRAS/RAF driven tumors like melanoma and colorectal cancer. GDC-0623 is a potent ATP-noncompetitive allosteric MEK1 inhibitor. The compound forms a strong hydrogen bond with Ser212 of MEK1, blocking MEK feedback phosphorylation of wild-type RAF. Preclinical studies showed efficacy in vitro and in vivo and in a phase I clinical study, suggesting that the compound has clinical potential. In the present work, we aimed to define candidate tumors to GDC-0623 treatment and gain insight into biomarkers and predictive models of response. GDC-0623 was tested in vitro in a 2D monolayer assay (260 human tumor cell lines of 36 histological subtypes). Next, activity was tested in vivo in a human tumor cell line engrafted subcutaneously in nude mice. Drug sensitivity results were then bound to molecular information of the tumor models, including whole exome mutations, gene copy number variations and gene expression profiles, to identify determinants and build a predictor of response. In vitro, GDC-0623 showed a strong anti-tumor activity (abs. IC70 & lt;1 µM) in a wide range of blood and solid tumors. IC50 values varied from 0.001 to & gt;30 µM (Geometric mean: 2.95 µM). The majority of leukemia CML and AML cell lines were sensitive (4/7 and 6/11, respectively) whereas lymphoma cell lines were mainly resistant. In solid tumors, strong activity was seen in almost all melanoma cell lines (10/12) and similar activity was observed in 5/8 bladder, 10/16 colon, 7/12 head and neck, 5/12 pancreas, 4/12 gastric and 4/12 breast cell lines. Anti-tumor activity of GDC-0623 was confirmed in vivo in the human colon HTX model COLO-205 (BRAF V600E mutant). An oral dose of 40 mg/kg/day caused a strong inhibition of the tumor growth (T/C = 6%) without impacting animal body weight. Screening of cell lines for molecular features associated with response showed BRAF V600E, NRAS Q61K, Q61R and DUSP27 gene mutations among the strongest predictors of response (Fisher test, p & lt;0.05). Furthermore, cell lines with EGFR and MET amplifications were almost all sensitive (4/5 and 3/4, respectively, Fisher p & lt;0.03). At transcriptome levels, a total 2108 genes were significantly associated with response to GDC-0623 (intersection of Spearman and Limma tests, adjusted p values & lt;0.05). Integrative analysis with significant genomic and transcriptomic parameters is currently ongoing to develop a molecular predictor of response to GDC-0623. Extending evaluation of the compound in vivo and validating predictors of response are needed to complete these preclinical investigations. Citation Format: Vincent Vuaroqueaux, Hoor Al Hasani, Gerhard Kelter, Hans R Hendriks, Heinz-Herbert Fiebig. Strong anti-tumor activity of MEK inhibitor GDC-0623 and determination of predictive biomarkers [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 2196.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2196
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Abstract 1173: Identification of novel targets for the treatment of pancreatic cancer patients
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1173-1173
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1173-1173
    Abstract: Pancreatic cancer (PC) is the 12th most common cancer worldwide. Despite a large panel of chemo- and targeted therapeutics options, patient prognosis remains poor with a 5-years overall survival below 10%. Thus, there is still a critical need to develop more efficient therapeutic alternatives. Antibody drug conjugates (ADC) and small molecule drug conjugates (SMDC) combine the oncolytic activity of highly potent chemotherapies with the target specificity of an antibody or a small molecule. Both ADC and SMDC are of increasing interest for cancer treatment, as they allow more specific delivery of chemotherapies to the tumor site. Facing the clinical needs for PC treatment, here we present an in-silico analysis to reveal specific targets for further ADC/SMDC development. 4HF Biotec has developed a proprietary platform connecting large clinical, OMICS and drug sensitivity data from various sources. It includes annotation for more than 1,800 preclinical models (cell lines, cell line-derived xenografts, and patient-derived xenografts), up to 11,000 patient tumors and 22,000 normal tissues (TCGA, GTEx and various GEO datasets). For tumor target discovery purposes, we designed and implemented the platform with specific analytics tools. To identify specific targets for PC, we first decided to analyze preclinical models, to focus on genes expressed by tumor cells and not by stroma cells. This aspect is particularly important in the context of PC which often have a high stroma content. Differential gene expression analysis of 113 PC preclinical models versus 1,737 tumor models from up to 30 tumor entities revealed 327 PC specific genes potentially targetable. Then, a similar analysis was performed by testing TCGA patient tumors (179 pancreatic tumors vs 9,521 patient tumors from other entities) and revealed 1,292 pancreatic specific genes. Finally, PC patient tumors were compared to 709 samples from various normal organs allowing to identify 1,156 tumor specific genes. At the intersection of these three analyses, we identified 56 PC-specific target candidates for ADC/SMDC development. Among the top candidates, MUCL3 (mucin like 3) was one of the most promising genes. Its mRNA expression is almost exclusively restricted to pancreatic and stomach samples in both preclinical models and TCGA patient tumors. It is overall not frequently expressed by normal tissues, and restricted to subsets of stomach, esophagus, and lung samples. The gene encodes for a transmembrane protein with a long weakly glycosylated extracellular part. A detailed analysis of the protein characteristics and expression modalities will be shown. The present work demonstrates that our in silico platform helps to identify promising targets for PC treatment using ADC/SMDC approaches. Our analyses revealed MUCL3 as one of the top candidates, further analyses will be needed to determine its druggability using small molecules or antibodies. Citation Format: Anne-Lise Peille, Alexandra Musch, Hoor Al-Hasani, Heinz-Herbert Fiebig, Vincent Vuaroqueaux. Identification of novel targets for the treatment of pancreatic cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1173.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1173
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Abstract 2879: MACC1 overexpression in colorectal cancer is driven by chromosomal instability and is associated with molecular subtype
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2879-2879
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2879-2879
    Abstract: Metastasis-Associated in Colon Cancer 1 (MACC1) is a strong prognostic marker for human colorectal cancers (CRC). The gene is a key regulator of the HGF/c-Met pathway and its overexpression is associated with cancer cell proliferation, migration, invasiveness and metastasis. The contexture of MACC1 overexpression in cancers is still poorly understood. Here we used the data released by The Cancer Genome Atlas (TCGA) and in silico approaches for a deep and integrative analysis of MACC1 expression modalities in CRCs. First, we curated COAD-READ TCGA datasets and obtained full clinical, genomic, and transcriptomic annotation for a total of 259 CRC samples. In tumors, we showed high heterogeneity of MACC1 mRNA expression levels with data varying from 5.58 to 13.07 U (RNAseq log transformed data - RSEM normalized). By correlating MACC1 expression to clinical data, we showed its levels were associated with anatomic regions of the disease (p=6.35.10-5). The tumors from descending colon and rectum having higher levels than those of the ascending colon and caecum (p=7.44-06). High MACC1 was also associated with higher tumor stages (p=0.01) and nodal invasion (p=0.03). At genomic level, MACC1 mutation was not frequent in CRCs ( & lt;2%). The gene is however frequently subjected to gene copy number variation (CNV) due to chromosomal instability and polyploidy (MACC1 CNV values & gt; normal in 155/259: 60%). Correlation analysis indicated strong positive association between MACC1 copy number variations and mRNA expression levels (p & lt;10-16). In an independent dataset, we validate that gain of MACC1 gene copy number and associated higher expression levels correlated with metastasis dissemination and worse outcome of the patients. By analyzing MACC1 with respect of CRC subtypes, we confirmed higher MACC1 levels in MSS tumors with high chromosomal instability (CIN) compared to MSI or genomic stable tumors (GS) (p=1.16-14). Regarding association with CMS1-4 transcriptomic subtypes, the highest expression of MACC1 were observed in CMS2-(epithelial), and CMS4 (mesenchymal) as compared with CMS3 (epithelial with metabolic dysregulation) or CMS1 (MMR deficient). The subset of tumors with very low MACC1 expression were mainly those altered for MLH1 (MSI-H- MMR tumors), notably most of them have normal ploidy. Deconvolution analysis of immune contexture revealed negative correlation between MACC1 expression and immune activation. Stratification using MACC1 as prognostic marker within these tumor types will be evaluated and the gene will also be presented with respect of alterations of key cancer genes in these tumors. Overall, the present study gives insight into the contexture of MACC1 expression in CRC. We showed MACC1 overexpression is largely driven by chromosomal instability and DNA copy number gains. Its expression was dependent on the tumor molecular subtypes. Citation Format: Vincent Vuaroqueaux, Hoor Al-Hasani, Dennis Kobelt, Thomas Risch, Susen Burock, Marie-Laure Yaspo, Heinz-Herbert Fiebig, Ulrike Stein. MACC1 overexpression in colorectal cancer is driven by chromosomal instability and is associated with molecular subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2879.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2879
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Abstract LB107: Identification of a promising renal cell carcinoma target using a unique in silico approach
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB107-LB107
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB107-LB107
    Abstract: In 2020, kidney cancers accounted for more than 4.1% of new cancer cases worldwide. Among these, more than 90% were renal cell carcinoma (RCC), a very heterogenous disease consisting of 3 major subtypes: chromophobe , papillary and clear cell. These subtypes differ in histology, genetic alterations, clinical outcome and therapeutic response. Over the last decades, great advances in the treatment of RCC have been made with additional targeting agents inhibiting RTKs, VEGFR and mTORC1. However, for local RCC surgery remains the main treatment modality whereas metastatic RCC is still difficult to treat due to chemoresistance. Antibody drug conjugates (ADC) or small molecule drug conjugates (SMDC) are emerging approaches for the treatment of cancer patients. By coupling highly potent chemotherapeutic agents to a specific antibody/small molecule, tumor cells can be selectively targeted allowing treatment with higher drug doses leading to an enhanced efficacy, while maintaining low toxicity in healthy tissues. 4HF Biotec has developed a proprietary database containing, among others, curated molecular data from tumor patient samples, preclinical models (cell lines, cell line-derived xenografts, and patient-derived xenografts) and normal tissues. Using this platform, we established a unique methodology to identify and prioritize genes that could be targeted by ADCs/SMDCs. By performing bioinformatics analyses of this molecular data, we identified genes that are differentially expressed across cancer (sub)types. We further selected those that are overexpressed in the tumor entity compared to matching normal tissue and in the tumor entity compared to all normal tissues. The overlapping genes were assessed in preclinical models to confirm their tumor-specificity. For the final selection, we investigated target druggability by curating data regarding protein function, targetability and localization. With this approach, we identified a total of 374 potential drug targets across 15 cancer (sub)types for the development of ADCs or SMDCs. Analyses of kidney cancer identified Semaphorin 5B (SEMA5B) among the top candidates. SEMA5B was significantly upregulated in patient samples of the kidney compared to other tumor entities. Comparison with normal kidney samples revealed a significant higher expression in tumor samples. In addition to the expression profiles, association between SEMA5B expression and clinical and molecular features will be presented. Furthermore, we will present curated information about protein function and structure that will facilitate antibody generation. Our findings indicate that targeting SEMA5B on tumor cells could represent a new therapeutic option in the treatment of renal cancer. Citation Format: Alexandra Musch, Anne-Lise Peille, Hoor Al Hasani, Heinz-Herbert Fiebig, Vincent Vuaroqueaux. Identification of a promising renal cell carcinoma target using a unique in silico approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB107.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-LB107
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Dissecting the genetics of the human transcriptome identifies novel trait-related trans -eQTLs and corroborates the regulatory relevance of non-protein coding loci
    Oxford University Press (OUP) ; 2015
    In:  Human Molecular Genetics Vol. 24, No. 16 ( 2015-08-15), p. 4746-4763
    Details
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 24, No. 16 ( 2015-08-15), p. 4746-4763
    Type of Medium: Online Resource
    ISSN: 0964-6906 , 1460-2083
    URL: Article
    DOI: 10.1093/hmg/ddv194
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2015
    detail.hit.zdb_id: 1474816-2
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    RELACS nuclei barcoding enables high-throughput ChIP-seq
    Springer Science and Business Media LLC ; 2018
    In:  Communications Biology Vol. 1, No. 1 ( 2018-12-05)
    Details
    In: Communications Biology, Springer Science and Business Media LLC, Vol. 1, No. 1 ( 2018-12-05)
    Abstract: Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) is an invaluable tool for mapping chromatin-associated proteins. Current barcoding strategies aim to improve assay throughput and scalability but intense sample handling and lack of standardization over cell types, cell numbers and epitopes hinder wide-spread use in the field. Here, we present a barcoding method to enable high-throughput ChIP-seq using common molecular biology techniques. The method, called RELACS (restriction enzyme-based labeling of chromatin in situ) relies on standardized nuclei extraction from any source and employs chromatin cutting and barcoding within intact nuclei. Barcoded nuclei are pooled and processed within the same ChIP reaction, for maximal comparability and workload reduction. The innovative barcoding concept is particularly user-friendly and suitable for implementation to standardized large-scale clinical studies and scarce samples. Aiming to maximize universality and scalability, RELACS can generate ChIP-seq libraries for transcription factors and histone modifications from hundreds of samples within three days.
    Type of Medium: Online Resource
    ISSN: 2399-3642
    URL: Article
    DOI: 10.1038/s42003-018-0219-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2919698-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers
    Springer Science and Business Media LLC ; 2021
    In:  npj Precision Oncology Vol. 5, No. 1 ( 2021-10-28)
    Details
    In: npj Precision Oncology, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2021-10-28)
    Abstract: MI-773 is a recently developed small-molecule inhibitor of the mouse double minute 2 (MDM2) proto-oncogene. Preclinical data on the anti-tumour activity of MI-773 are limited and indicate that tumour cell lines (CLs) with mutated TP53 are more resistant to MI-773 than wild type TP53 . Here, we explored the compound’s therapeutic potential in vitro using a panel of 274 annotated CLs derived from a diversity of tumours. MI-773 exhibited a pronounced selectivity and moderate potency, with anti-tumour activity in the sub-micromolar range in about 15% of the CLs. The most sensitive tumour types were melanoma, sarcoma, renal and gastric cancers, leukaemia, and lymphoma. A COMPARE analysis showed that the profile of MI-773 was similar to that of Nutlin-3a, the first potent inhibitor of p53–MDM2 interactions, and, in addition, had a superior potency. In contrast, it poorly correlates with profiles of compounds targeting the p53 pathway with another mechanism of action. OMICS analyses confirmed that MI-773 was primarily active in CLs with wild type TP53 . In silico biomarker investigations revealed that the TP53 mutation status plus the aggregated expression levels of 11 genes involved in the p53 signalling pathway predicted sensitivity or resistance of CLs to inhibitors of p53–MDM2 interactions reliably. The results obtained for MI-773 could help to refine the selection of cancer patients for therapy.
    Type of Medium: Online Resource
    ISSN: 2397-768X
    URL: Article
    DOI: 10.1038/s41698-021-00235-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2891458-2
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    Abstract C060: Broad spectrum activity of the MDM2 inhibitor MI-773 in hematologic and solid cancer cell lines in-vitro and determination of predictive biomarkers
    American Association for Cancer Research (AACR) ; 2019
    In:  Molecular Cancer Therapeutics Vol. 18, No. 12_Supplement ( 2019-12-01), p. C060-C060
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 18, No. 12_Supplement ( 2019-12-01), p. C060-C060
    Abstract: The Mouse Double Minute 2 (MDM2) proto-oncogene is a primary cellular inhibitor of p53 tumor suppressor protein. MDM2 encodes for a nuclear-localized E3 ubiquitin-protein ligase via direct interaction responsible for proteasomal degradation of p53. Its overexpression in TP53 wild type tumors leads to the loss of apoptotic function and cell survival. MDM2 inhibitors were envisioned to restore p53 activity in p53 wild type tumors, several are currently being evaluated in the clinic. MI-773 is a small molecule, that inhibits the p53-MDM2 protein-protein interaction. It has been evaluated in Phase I. We aimed to pursue characterization of MI-773’s anti-tumor activity by performing a large pharmacogenomic study to identify tumor candidates for such treatment. MI-773 was tested in vitro in a 2D monolayer assay in 274 human tumor cell lines (50 hematologic and 224 solid cancer cell lines) belonging to 36 tumor types. Drug sensitivity results in vitro were correlated with molecular data of the cell lines, including whole exome mutations, gene copy number variations and gene expression profiles, to study molecular determinants for a response. MI-773 showed a moderate anti-tumor potency (median IC50 13,5 µM, range 0.1 to up to30 µM) and pronounced selectivity was observed in several hematologic and solid cancer cell lines. Fifty tumor cell lines (18,5%) were 10 times more sensitive compared to the median IC50 of all cell lines. Among the solid cell lines, melanomas, kidney, stomach, breast and pleural mesotheliomas were the most sensitive tumor types, whereas ALL, AML, and multiple myelomas were the most sensitive hematological tumors. Confirmatory in vivo studies of MI-773 in the most sensitive tumors are planned. The Compare analysis of MI-773 with 44 targeted agents and 250 cytotoxic agents in 40 to 117 tumor cell lines showed the highest similarity with p53/MDM2 inhibitors Nutlin-3a and YH239-EE with Spearman correlation coefficients of 0,71 and 0,56, a clear indication that biological testing’s in cell line panels allows identification of the mechanism of action of novel compounds. As expected, TP53 mutation was the major determinant of tumor sensitivity to MI-773 (Wilcoxon test, adjusted p value= 2;28E-12). Sixty one out of 88 (69%) tumor cell lines wild type TP53 showed a high sensitivity to MI-773 whereas 141 out of 162 (87%) cell lines mutated for the gene were resistant. Transcriptome analysis revealed that the expression levels of 355 genes were significantly associated with sensitivity to MI-773 (LIMMA and Spearman test adjusted p values both p & lt;0.05). MDM2, CDKN1A, SPATA18 and ZMAT3 were the strongest predictors positively associated with both TP53 integrity and sensitivity toward MI-773. Pathway analysis confirmed that overall the genes upregulated in tumor cell lines sensitive to MI-773 to be dominantly involved in negative regulation of mitotic cell cycle, regulation of cell cycle phase transition or signal transduction by p53 class mediator. The present study demonstrated that the MDM2 inhibitor MI-773 could be used in a broad range of hematological and solid tumor types, however, with the determination of TP53 as a prerequisite. MDM2 inhibitors should be evaluated in p53 wild type melanomas, mesotheliomas, kidney, stomach, and breast cancers as well as in ALL, AML, and multiple myelomas. Citation Format: Heinz-Herbert Fiebig, Gerhard Kelter, Hans R Hendriks, Hoor Al Hasani, Vincent Vuaroqueaux. Broad spectrum activity of the MDM2 inhibitor MI-773 in hematologic and solid cancer cell lines in-vitro and determination of predictive biomarkers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C060. doi:10.1158/1535-7163.TARG-19-C060
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-19-C060
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...