Browsing Molecular Pathology by author "Lord, Christopher"
Now showing items 61-80 of 81
-
Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors.
Yap, TA; O'Carrigan, B; Penney, MS; Lim, JS; Brown, JS; et al. (AMER SOC CLINICAL ONCOLOGY, 2020-06-22)PURPOSE: Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging ... -
Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non-BRCA1/2-Mutant Cancers.
Yap, TA; Kristeleit, R; Michalarea, V; Pettitt, SJ; Lim, JSJ; et al. (AMER ASSOC CANCER RESEARCH, 2020-10-01)Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)-deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing ... -
Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes.
Fleuren, EDG; Vlenterie, M; van der Graaf, WTA; Hillebrandt-Roeffen, MHS; Blackburn, J; et al. (AMER ASSOC CANCER RESEARCH, 2017-08-15)Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical ... -
Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
Zatreanu, D; Robinson, HMR; Alkhatib, O; Boursier, M; Finch, H; et al. (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 ... -
Quantitative Assessment and Prognostic Associations of the Immune Landscape in Ovarian Clear Cell Carcinoma.
Khalique, S; Nash, S; Mansfield, D; Wampfler, J; Attygale, A; et al. (MDPI, 2021-07-30)Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian cancer characterised by a high frequency of loss-of-function ARID1A mutations and a poor response to chemotherapy. Despite their generally low ... -
Sirtuin inhibition is synthetic lethal with BRCA1 or BRCA2 deficiency.
Bajrami, I; Walker, C; Krastev, DB; Weekes, D; Song, F; et al. (NATURE PORTFOLIO, 2021-11-08)PARP enzymes utilise NAD+ as a co-substrate for their enzymatic activity. Inhibition of PARP1 is synthetic lethal with defects in either BRCA1 or BRCA2. In order to assess whether other genes implicated in NAD+ metabolism ... -
Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma.
Beck, D; Zobel, J; Barber, R; Evans, S; Lezina, L; et al. (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2016-08-05)We demonstrate the usefulness of synthetic lethal screening of a conditionally BCL6-deficient Burkitt lymphoma cell line, DG75-AB7, with a library of small molecules to determine survival pathways suppressed by BCL6 and ... -
Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib.
Miller, RE; Brough, R; Bajrami, I; Williamson, CT; McDade, S; et al. (AMER ASSOC CANCER RESEARCH, 2016-07-01)New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based ... -
Synthetic lethal therapies for cancer: what's next after PARP inhibitors?
Ashworth, A; Lord, CJ (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 ... -
Synthetic Lethality and Cancer - Penetrance as the Major Barrier.
Ryan, CJ; Bajrami, I; Lord, CJ (CELL PRESS, 2018-10-01)Synthetic lethality has long been proposed as an approach for targeting genetic defects in tumours. Despite a decade of screening efforts, relatively few robust synthetic lethal targets have been identified. Improved genetic ... -
Synthetic lethality: the road to novel therapies for breast cancer.
Dhillon, KK; Bajrami, I; Taniguchi, T; Lord, CJ (BIOSCIENTIFICA LTD, 2016-10-01)When the BRCA1 and BRCA2 tumour suppressor genes were identified in the early 1990s, the immediate implications of mapping, cloning and delineating the sequence of these genes were that individuals in families with a BRCA ... -
Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer.
Witkiewicz, AK; Chung, S; Brough, R; Vail, P; Franco, J; et al. (CELL PRESS, 2018-01-30)Approximately 30% of triple-negative breast cancers (TNBCs) exhibit functional loss of the RB tumor suppressor, suggesting a target for precision intervention. Here, we use drug screens to identify agents specifically ... -
Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer.
Yeow, ZY; Lambrus, BG; Marlow, R; Zhan, KH; Durin, M-A; et al. (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 ... -
The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells.
Barazas, M; Annunziato, S; Pettitt, SJ; de Krijger, I; Ghezraoui, H; et al. (CELL PRESS, 2018-05-15)Selective elimination of BRCA1-deficient cells by inhibitors of poly(ADP-ribose) polymerase (PARP) is a prime example of the concept of synthetic lethality in cancer therapy. This interaction is counteracted by the restoration ... -
The cylindromatosis gene product, CYLD, interacts with MIB2 to regulate notch signalling.
Rajan, N; Elliott, RJR; Smith, A; Sinclair, N; Swift, S; et al. (IMPACT JOURNALS LLC, 2014-12-15)CYLD, an ubiquitin hydrolase, has an expanding repertoire of regulatory roles in cell signalling and is dysregulated in a number of cancers. To dissect CYLD function we used a proteomics approach to identify CYLD interacting ... -
The Mutational Concordance of Fixed Formalin Paraffin Embedded and Fresh Frozen Gastro-Oesophageal Tumours Using Whole Exome Sequencing.
Chong, IY; Starling, N; Rust, A; Alexander, J; Aronson, L; et al. (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 ... -
The shieldin complex mediates 53BP1-dependent DNA repair.
Noordermeer, SM; Adam, S; Setiaputra, D; Barazas, M; Pettitt, SJ; et al. (NATURE PUBLISHING GROUP, 2018-08-02)53BP1 is a chromatin-binding protein that regulates the repair of DNA double-strand breaks by suppressing the nucleolytic resection of DNA termini1,2. This function of 53BP1 requires interactions with PTIP3 and RIF14-9, ... -
The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin.
Krastev, DB; Li, S; Sun, Y; Wicks, AJ; Hoslett, G; et al. (NATURE PORTFOLIO, 2022-01-01)Poly (ADP-ribose) polymerase (PARP) inhibitors elicit antitumour activity in homologous recombination-defective cancers by trapping PARP1 in a chromatin-bound state. How cells process trapped PARP1 remains unclear. Using ... -
Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma.
George, SL; Lorenzi, F; King, D; Hartlieb, S; Campbell, J; et al. (ELSEVIER, 2020-09-01)BACKGROUND: In neuroblastoma, genetic alterations in ATRX, define a distinct poor outcome patient subgroup. Despite the need for new therapies, there is a lack of available models and a dearth of pre-clinical research. ... -
Three-dimensional modelling identifies novel genetic dependencies associated with breast cancer progression in the isogenic MCF10 model.
Maguire, SL; Peck, B; Wai, PT; Campbell, J; Barker, H; et al. (WILEY, 2016-11-01)The initiation and progression of breast cancer from the transformation of the normal epithelium to ductal carcinoma in situ (DCIS) and invasive disease is a complex process involving the acquisition of genetic alterations ...