A5050305179- PARP inhibition in cancer therapy
- DNA Repair Mechanisms
- Chromatin Remodeling and Cancer
- Cancer Mechanisms and Therapy
- CRISPR and Genetic Engineering
- Glioma Diagnosis and Treatment
- Animal Virus Infections Studies
- Ovarian cancer diagnosis and treatment
- Cancer-related gene regulation
- PI3K/AKT/mTOR signaling in cancer
- Cancer, Hypoxia, and Metabolism
- Research on Leishmaniasis Studies
- Cancer Genomics and Diagnostics
- Growth Hormone and Insulin-like Growth Factors
- Cancer-related Molecular Pathways
- BRCA gene mutations in cancer
- Cytokine Signaling Pathways and Interactions
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Monoclonal and Polyclonal Antibodies Research
- Estrogen and related hormone effects
- Kruppel-like factors research
- Pancreatic and Hepatic Oncology Research
- RNA Interference and Gene Delivery
- Bioinformatics and Genomic Networks
The Francis Crick Institute
2020-2024
Breast Cancer Now
2013-2023
Institute of Cancer Research
2012-2023
Cancer Research UK
2012-2020
University of Minho
2013
Jilin University
2013
University of Portsmouth
2013
Washington University in St. Louis
2013
Duke Medical Center
2013
University of Coimbra
2013
Abstract Purpose: PARP1/2 inhibitors are a class of anticancer agents that target tumor-specific defects in DNA repair. Here, we describe BMN 673, novel, highly potent inhibitor with favorable metabolic stability, oral bioavailability, and pharmacokinetic properties. Experimental Design: Potency selectivity 673 was determined by biochemical assays. Anticancer activity either as single-agent or combination other antitumor evaluated both vitro xenograft cancer models. Results: is (PARP1 IC50 =...
Small-molecule inhibitors of PARP1/2, such as olaparib, have been proposed to serve a synthetic lethal therapy for cancers that harbor BRCA1 or BRCA2 mutations. Indeed, in clinical trials, PARP1/2 elicit sustained antitumor responses patients with germline BRCA gene In hypothesizing additional genetic determinants might direct use these drugs, we conducted genome-wide screen candidate olaparib sensitivity genes. support this hypothesis, the set identified genes included known sensitivity,...
Abstract Children and young adults with glioblastoma (GBM) have a median survival rate of only 12 to 15 months, these GBMs are clinically biologically distinct from histologically similar cancers in older adults. They defined by highly specific mutations the gene encoding histone H3.3 variant H3F3A, occurring either at or close key residues marked methylation for regulation transcription—K27 G34. Here, we show that cerebral hemisphere-specific G34 mutation drives expression signature through...
The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non–small lung (NSCLC) exhibit an enhanced type I transcriptomic signature low expression correlates increased...
Abstract RAD52 is important for the repair of DNA double-stranded breaks 1,2 , mitotic synthesis 3–5 and alternative telomere length maintenance 6,7 . Central to these functions, promotes annealing complementary single-stranded (ssDNA) 8,9 provides an BRCA2/RAD51-dependent homologous recombination 10 Inactivation in homologous-recombination-deficient BRCA1 - or BRCA2 -defective cells synthetically lethal 11,12 aberrant expression associated with poor cancer prognosis 13,14 As a consequence,...
Genetic perturbation screens have the potential to dissect a wide range of cellular phenotypes. Such historically been difficult in diploid mammalian cells. The recent derivation haploid embryonic stem cells provides an opportunity cause loss function mutants with random mutagen cell normal genetic background. We describe approach that exploits highly active piggyBac transposon As example (HTP) screening, we apply this identifying determinants cancer drug toxicity and resistance. In screen...
Abstract The design of targeted therapeutic strategies for cancer has largely been driven by the identification tumor-specific genetic changes. However, large number alterations present in tumor cells means that it is difficult to discriminate between genes are critical maintaining disease state and those merely coincidental. Even when can be identified, directly targeting these often challenging, meaning alternative such as exploiting synthetic lethality may beneficial. To address issues,...
Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set become second leading cause of death in our society. The study aim was investigate association between DNA damage response (DDR), replication stress, and novel therapeutic PC develop a biomarker-driven strategy targeting DDR stress PC.
Abstract The cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens tumor cells with CRISPR/Cas9-engineered CDH1 mutations, we identified synthetic lethality between deficiency and inhibition of the tyrosine kinase ROS1. Data from large-scale genetic molecularly diverse lines established E-cadherin/ROS1 was only robust face considerable molecular...
Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these are driven by distinct metabolic phenotypes. Loss of genes drive endodermal lineage specification, HNF4A GATA6, switch profiles from predominantly squamous, glycogen synthase kinase 3 beta (GSK3β) a key regulator glycolysis. Pharmacological inhibition GSK3β results in selective sensitivity the squamous subtype;...
One approach to identifying cancer-specific vulnerabilities and therapeutic targets is profile genetic dependencies in cancer cell lines. Here, we describe data from a series of siRNA screens that identify the kinase 117 lines ten types. By integrating screen with molecular profiling data, including exome sequencing show how vulnerabilities/genetic are associated mutations specific driver genes can be identified. additional sets into this analysis, protein-protein interaction also...
Abstract Micropapillary carcinoma ( MPC ) is a rare histological special type of breast cancer, characterized by an aggressive clinical behaviour and pattern copy number aberrations CNAs distinct from that grade‐ oestrogen receptor ER )‐matched invasive carcinomas no IC‐NSTs ). The aims this study were to determine whether MPCs are underpinned recurrent fusion gene(s) or mutations in 273 genes recurrently mutated cancer. Sixteen subjected microarray‐based comparative genomic hybridization...
Three strikes to knock cancer out BRCA1 and BRCA2 are tumor-suppressor genes, patients with mutations in these genes predisposed breast, ovarian, other cancers. Because affect pathways involved DNA break repair, patients' tumors usually vulnerable treatments that further damage such as poly(ADP-ribose) polymerase (PARP) inhibitors, but they can acquire resistance therapy. Using a genome-wide screening approach, Fugger et al. identified protein called DNPH1 “nucleotide sanitizer” prevents the...
Abstract Inactivation of Polybromo 1 (PBRM1), a specific subunit the PBAF chromatin remodeling complex, occurs frequently in cancer, including 40% clear cell renal carcinomas (ccRCC). To identify novel therapeutic approaches to targeting PBRM1-defective cancers, we used series orthogonal functional genomic screens that identified PARP and ATR inhibitors as being synthetic lethal with PBRM1 deficiency. The PBRM1/PARP inhibitor lethality was recapitulated using several clinical vitro model...
Abstract New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and poor response standard chemotherapy. Using a series of high-throughput cell-based drug screens OCCC tumor models, we have identified synthetic lethal (SL) interaction between kinase inhibitor dasatinib key driver OCCC, ARID1A mutation. Imposing deficiency upon variety human or mouse cells induced sensitivity, both vitro vivo, suggesting that is robust...
Abstract WEE1 kinase regulates CDK1 and CDK2 activity to facilitate DNA replication during S-phase prevent unscheduled entry into mitosis. inhibitors synergize with DNA-damaging agents that arrest cells in by triggering direct mitotic without completing synthesis, resulting catastrophic chromosome fragmentation apoptosis. Here, we investigated how inhibition could be best exploited for cancer therapy performing a functional genetic screen identify novel determinants of sensitivity...
Protein complexes are responsible for the bulk of activities within cell, but how their behavior and abundance varies across tumors remains poorly understood. By combining proteomic profiles breast with a large-scale protein-protein interaction network, we have identified set 285 high-confidence protein whose subunits highly correlated tumor samples. We used this to identify that reproducibly under- or overexpressed in specific cancer subtypes. found mutation deletion one subunit...
Drugs that inhibit insulin-like growth factor 1 (IGFI) receptor IGFIR were encouraging in early trials, but predictive biomarkers lacking and the drugs provided insufficient benefit unselected patients. In this study, we used genetic screening downstream validation to identify WNT pathway element DVL3 as a mediator of resistance inhibition. Sensitivity inhibition was enhanced specifically vitro vivo by or pharmacologic blockade DVL3. breast prostate cancer cells, sensitization tracked with...