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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 ...
Dissecting PARP inhibitor resistance with functional genomics.
(CURRENT BIOLOGY LTD, 2019-02-01)
The poly-(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib was the first licenced cancer drug that targeted an inherited form of cancer, namely ovarian cancers caused by germline BRCA1 or BRCA2 gene mutations. ...
Stromal cell ratio based on automated image analysis as a predictor for platinum-resistant recurrent ovarian cancer.
(BMC, 2019-02-18)
BACKGROUND: Identifying high-risk patients for platinum resistance is critical for improving clinical management of ovarian cancer. We aimed to use automated image analysis of hematoxylin & eosin (H&E) stained sections to ...
Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells.
(NATURE PUBLISHING GROUP, 2018-08-01)
BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome ...
Analysis of tumour ecological balance reveals resource-dependent adaptive strategies of ovarian cancer.
(ELSEVIER, 2019-10-21)
BACKGROUND: Despite treatment advances, there remains a significant risk of recurrence in ovarian cancer, at which stage it is usually incurable. Consequently, there is a clear need for improved patient stratification. ...
A decade of clinical development of PARP inhibitors in perspective.
(ELSEVIER, 2019-09-01)
Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce ...
Similarity and diversity of the tumor microenvironment in multiple metastases: critical implications for overall and progression-free survival of high-grade serous ovarian cancer.
(IMPACT JOURNALS LLC, 2016-11-01)
The tumor microenvironment is pivotal in influencing cancer progression and metastasis. Different cells co-exist with high spatial diversity within a patient, yet their combinatorial effects are poorly understood. We ...
Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer.
(IMPACT JOURNALS LLC, 2017-01-24)
PURPOSE: To determine if models of ovarian clear cell carcinomas (OCCCs) harbouring defects in homologous recombination (HR) DNA repair of double strand breaks (DSBs) are sensitive to cisplatin and/or PARP inhibition. ...
Microenvironmental niche divergence shapes BRCA1-dysregulated ovarian cancer morphological plasticity.
(NATURE RESEARCH, 2018-09-25)
How tumor microenvironmental forces shape plasticity of cancer cell morphology is poorly understood. Here, we conduct automated histology image and spatial statistical analyses in 514 high grade serous ovarian samples to ...
Synthetic lethal therapies for cancer: what's next after PARP inhibitors?
(NATURE PUBLISHING GROUP, 2018-06-28)
The genetic concept of synthetic lethality has now been validated clinically through the demonstrated efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of cancers in individuals with germline ...