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Wael Jdey - One of the best experts on this subject based on the ideXlab platform.

  • drug driven synthetic lethality bypassing tumor Cell Genetics with a combination of asidna and parp inhibitors
    Clinical Cancer Research, 2017
    Co-Authors: Wael Jdey, Sylvain Thierry, Christophe Russo, Flavien Devun, Muthana Al Abo, Patricia Noguiezhellin, Jiansheng Sun, Emmanuel Barillot
    Abstract:

    Purpose: Cancer treatments using tumor defects in DNA repair pathways have shown promising results but are restricted to small subpopulations of patients. The most advanced drugs in this field are PARP inhibitors (PARPi), which trigger synthetic lethality in tumors with homologous recombination (HR) deficiency. Using AsiDNA, an inhibitor of HR and nonhomologous end joining, together with PARPi should allow bypassing the genetic restriction for PARPi efficacy.Experimental Design: We characterized the DNA repair inhibition activity of PARPi (olaparib) and AsiDNA by monitoring repair foci formation and DNA damage. We analyzed the Cell survival to standalone and combined treatments of 21 tumor Cells and three nontumor Cells. In 12 breast cancer (BC) Cell lines, correlation with sensitivity to each drug and transcriptome were statistically analyzed to identify resistance pathways.Results: Molecular analyses demonstrate that olaparib and AsiDNA respectively prevent recruitment of XRCC1 and RAD51/53BP1 repair enzymes to damage sites. Combination of both drugs increases the accumulation of unrepaired damage resulting in an increase of Cell death in all tumor Cells. In contrast, nontumor Cells do not show an increase of DNA damage nor lethality. Analysis of multilevel omics data from BC Cells highlighted different DNA repair and Cell-cycle molecular profiles associated with resistance to AsiDNA or olaparib, rationalizing combined treatment. Treatment synergy was also confirmed with six other PARPi in development.Conclusions: Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status. Clin Cancer Res; 23(4); 1001-11. ©2016 AACR.

Davis J Mccarthy - One of the best experts on this subject based on the ideXlab platform.

  • cardelino computational integration of somatic clonal substructure and single Cell transcriptomes
    Nature Methods, 2020
    Co-Authors: Davis J Mccarthy, Raghd Rostom, Yuanhua Huang, Daniel J Kunz, Petr Danecek
    Abstract:

    Bulk and single-Cell DNA sequencing has enabled reconstructing clonal substructures of somatic tissues from frequency and cooccurrence patterns of somatic variants. However, approaches to characterize phenotypic variations between clones are not established. Here we present cardelino (https://github.com/single-Cell-Genetics/cardelino), a computational method for inferring the clonal tree configuration and the clone of origin of individual Cells assayed using single-Cell RNA-seq (scRNA-seq). Cardelino flexibly integrates information from imperfect clonal trees inferred based on bulk exome-seq data, and sparse variant alleles expressed in scRNA-seq data. We apply cardelino to a published cancer dataset and to newly generated matched scRNA-seq and exome-seq data from 32 human dermal fibroblast lines, identifying hundreds of differentially expressed genes between Cells from different somatic clones. These genes are frequently enriched for Cell cycle and proliferation pathways, indicating a role for Cell division genes in somatic evolution in healthy skin.

Marta Sanchezmartin - One of the best experts on this subject based on the ideXlab platform.

  • the subclonal complexity of stil tal1 t Cell acute lymphoblastic leukaemia
    Leukemia, 2018
    Co-Authors: Caroline L Furness, Marcela B Mansur, Victoria J Weston, Luca Ermini, Frederik W Van Delft, Sarah Jenkinson, Rosemary E Gale, Christine J Harrison, Maria S Pombodeoliveira, Marta Sanchezmartin
    Abstract:

    Single-Cell Genetics were used to interrogate clonal complexity and the sequence of mutational events in STIL-TAL1+ T-ALL. Single-Cell multicolour FISH was used to demonstrate that the earliest detectable leukaemia subclone contained the STIL-TAL1 fusion and copy number loss of 9p21.3 (CDKN2A/CDKN2B locus), with other copy number alterations including loss of PTEN occurring as secondary subclonal events. In three cases, multiplex qPCR and phylogenetic analysis were used to produce branching evolutionary trees recapitulating the snapshot history of T-ALL evolution in this leukaemia subtype, which confirmed that mutations in key T-ALL drivers, including NOTCH1 and PTEN, were subclonal and reiterative in distinct subclones. Xenografting confirmed that self-renewing or propagating Cells were genetically diverse. These data suggest that the STIL-TAL1 fusion is a likely founder or truncal event. Therapies targeting the TAL1 auto-regulatory complex are worthy of further investigation in T-ALL.

Robert G Bristow - One of the best experts on this subject based on the ideXlab platform.

  • contextual synthetic lethality and or loss of heterozygosity tumor hypoxia and modification of dna repair
    Clinical Cancer Research, 2010
    Co-Authors: Norman Chan, Robert G Bristow
    Abstract:

    Hypoxia exists in every solid tumor and is associated with poor prognosis because of both local and systemic therapeutic resistance. Recent studies have focused on the interaction between tumor Cell Genetics and the dynamic state of oxygenation and metabolism. Hypoxia generates aggressive tumor Cell phenotypes in part owing to ongoing genetic instability and a "mutator" phenotype. The latter may be due to suppression of DNA mismatch repair (MMR), nucleotide excision repair (NER), and double-strand break (DSB) repair. We propose a theoretical model in which hypoxia-mediated defects in DNA repair can lead to "contextual loss of heterozygosity" and drive oncogenesis. Additionally, hypoxia-mediated repair defects can be specifically targeted by DNA damaging agents and/or "contextual synthetic lethality" to kill repair-deficient Cells and preserve the therapeutic ratio. These proposed concepts support the interrogation of solid tumors to document repair defects in both oxic and hypoxic tumor subregions as a conduit to novel clinical trials within the context of personalized medicine.

Gregory J Hannon - One of the best experts on this subject based on the ideXlab platform.