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Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
(NATURE RESEARCH, 2021-06-17)
To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ...
Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer.
(NATURE PORTFOLIO, 2020-09-17)
Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer1,2. The success of poly-ADP ribose polymerase inhibitors in the treatment of breast cancers that are ...
PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.
(AMER SOC CLINICAL INVESTIGATION INC, 2019-03-01)
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 DNA ...
Clinical BRCA1/2 Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance.
(AMER ASSOC CANCER RESEARCH, 2020-10-01)
Reversion mutations in BRCA1 or BRCA2 are associated with resistance to PARP inhibitors and platinum. To better understand the nature of these mutations, we collated, codified, and analyzed more than 300 reversions. This ...
Real-time ex vivo perfusion of human lymph nodes invaded by cancer (REPLICANT): a feasibility study.
(WILEY, 2020-03-01)
Understanding how breast cancer (BC) grows in axillary lymph nodes (ALNs), and refining how therapies might halt that process, is clinically important. However, modelling the complex ALN microenvironment is difficult, and ...
Capture Hi-C identifies putative target genes at 33 breast cancer risk loci.
(NATURE PUBLISHING GROUP, 2018-03-12)
Genome-wide association studies (GWAS) have identified approximately 100 breast cancer risk loci. Translating these findings into a greater understanding of the mechanisms that influence disease risk requires identification ...
Evaluation of CDK12 Protein Expression as a Potential Novel Biomarker for DNA Damage Response-Targeted Therapies in Breast Cancer.
(AMER ASSOC CANCER RESEARCH, 2018-01-01)
Disruption of Cyclin-Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and PARP1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. ...
The Mutational Concordance of Fixed Formalin Paraffin Embedded and Fresh Frozen Gastro-Oesophageal Tumours Using Whole Exome Sequencing.
(MDPI, 2021-01-09)
UNLABELLED: 1. BACKGROUND: The application of massively parallel sequencing has led to the identification of aberrant druggable pathways and somatic mutations within therapeutically relevant genes in gastro-oesophageal ...
Proteomics of REPLICANT perfusate detects changes in the metastatic lymph node microenvironment.
(NATURE PORTFOLIO, 2021-03-05)
In breast cancer (BC), detecting low volumes of axillary lymph node (ALN) metastasis pre-operatively is difficult and novel biomarkers are needed. We recently showed that patient-derived ALNs can be sustained ex-vivo using ...
3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer.
(AMER ASSOC CANCER RESEARCH, 2021-02-15)
Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies ...