Rucaparib: An emerging parp inhibitor for treatment of recurrent ovarian cancer

Musella, Angela; Bardhi, Erlisa; Marchetti, Cláudia; Vertechy, Laura; Santangelo, Giusi; Sassu, Carolina Maria; Tomao, Federica; Rech, F; D'Amelio, R; Monti, Marco; Palaia, Innocenza; Muzii, Ludovico; Panici, Pierluigi Benedetti

doi:10.1016/j.ctrv.2018.03.004

Cited by 51 publications

(32 citation statements)

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“…BRCA1/2 are key homologous recombination (HR) genes that play crucial roles in DNA double‐strand break repair. Ovarian cancer patients with BRCA1/2 mutations are known to respond better to platinum‐based chemotherapies and have longer overall survivals and they also benefit from PARP inhibitor which is currently the most important targeted therapy for HGSOC patients . The high prevalence of BRCA1/2 mutations, most of which were from germline samples, highlighted the importance of routine BRCA1/2 testing for Chinese ovarian cancer patients.…”

Section: Discussionmentioning

confidence: 99%

“…Ovarian cancer patients with BRCA1/2 mutations are known to respond better to platinum-based chemotherapies and have longer overall survivals 2,23 and they also benefit from PARP inhibitor which is currently the most important targeted therapy for HGSOC patients. 24 The high prevalence of BRCA1/2 mutations, most of which were from germline samples, highlighted the importance of routine BRCA1/2 testing for Chinese ovarian cancer patients. Several other tumors in the cohort also harbored mutations in other HR genes including ATM, RAC1, and RAD51C.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive genomic profiling of high‐grade serous ovarian carcinoma from Chinese patients identifies co‐occurring mutations in the Ras/Raf pathway with TP53

et al. 2019

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High‐grade serous ovarian carcinoma (HGSOC) is a major form of ovarian epithelial tumor that is often diagnosed only at an advanced stage when it is already highly aggressive. We performed comprehensive genomic profiling using an analytically validated clinical next‐generation sequencing assay to identify genomic alterations in 450 cancer‐related genes in a cohort of 88 Chinese HGSOC patients. Overall, we detected 547 genomic alterations with an average of 6.2 alterations per tumor. Most of these HGSOC tumors had low tumor mutation burden and were microsatellite stable. Consistent with earlier studies, TP53 mutations were present in the majority (96.6%) of the tumors studied, and mutations in BRCA1/2 that affect DNA repair were also detected frequently in 20.5% of the tumors. However, we observed a 10.2% of mutated genes in the Ras/Raf pathway, all co‐occurring with TP53 mutations in the same tumor, which was unrecognized previously. Our results show that in HGSOC patients, there may be an unrecognized co‐occurrence of TP53 mutations with mutations in Ras/Raf pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comprehensive genomic profiling of high‐grade serous ovarian carcinoma from Chinese patients identifies co‐occurring mutations in the Ras/Raf pathway with TP53

et al. 2019

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“…In fact, inhibitors of the PARP family of proteins are currently under preclinical and clinical evaluation as anticancer medication for melanoma and ovarian, breast and prostate cancer. PARPis have a peculiarity in that these drugs increase the efficacy of DNA-damaging agents to selectively target tumour cells with specific DNA repair defects (Musella et al 2018;Papeo et al 2013;Plummer et al 2013). Resistance of cancer cells to PARP inhibitors, however, is also beginning to occur and accurate biomarkers for treatment sensitivity and resistance remain challenging (Montoni et al 2013;Schlacher 2017).…”

Section: Proteogenomicsmentioning

confidence: 99%

Clinical protein science in translational medicine targeting malignant melanoma

et al. 2019

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Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry-based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive molecular characterisation of cellular

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“…This field of study was motivated in large part by earlier reports that DNA repair proteins (e.g., (PARP)) are inhibited by specific small molecules (e.g., olaparib in the case of PARP-1) which can be used to modulate DNA repair capacity in human cells, particularly in defined genetic backgrounds (BRCA) [403,404]. Such an approach is postulated to be a new methodology for anti-cancer therapy, and PARP inhibitors are being used in the clinic (e.g., olaparib [405], rucaparib [406]) or in clinical trials. Other DNA repair inhibitors are currently being investigated for their vulnerability to pharmacological inhibition by small molecules that interact with their targets [407].…”

Section: Small Molecule Modulation Of Dna Helicasesmentioning

confidence: 99%

History of DNA Helicases

Brosh

Matson

2020

Genes

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Since the discovery of the DNA double helix, there has been a fascination in understanding the molecular mechanisms and cellular processes that account for: (i) the transmission of genetic information from one generation to the next and (ii) the remarkable stability of the genome. Nucleic acid biologists have endeavored to unravel the mysteries of DNA not only to understand the processes of DNA replication, repair, recombination, and transcription but to also characterize the underlying basis of genetic diseases characterized by chromosomal instability. Perhaps unexpectedly at first, DNA helicases have arisen as a key class of enzymes to study in this latter capacity. From the first discovery of ATP-dependent DNA unwinding enzymes in the mid 1970’s to the burgeoning of helicase-dependent pathways found to be prevalent in all kingdoms of life, the story of scientific discovery in helicase research is rich and informative. Over four decades after their discovery, we take this opportunity to provide a history of DNA helicases. No doubt, many chapters are left to be written. Nonetheless, at this juncture we are privileged to share our perspective on the DNA helicase field – where it has been, its current state, and where it is headed.

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Rucaparib: An emerging parp inhibitor for treatment of recurrent ovarian cancer

Cited by 51 publications

References 46 publications

Comprehensive genomic profiling of high‐grade serous ovarian carcinoma from Chinese patients identifies co‐occurring mutations in the Ras/Raf pathway with TP53

Comprehensive genomic profiling of high‐grade serous ovarian carcinoma from Chinese patients identifies co‐occurring mutations in the Ras/Raf pathway with TP53

Clinical protein science in translational medicine targeting malignant melanoma

History of DNA Helicases

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