China
Africa
Explore chapters and articles related to this topic
Molecular Mediator of Prostate Cancer Progression and Its Implication in Therapy
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Samikshan Dutta, Navatha Shree Sharma, Ridwan Islam, Kaustubh Datta
TCGA database suggested mutations in many DNA repair genes like BRCA1, BRCA2, FANCD2, CKD12 and ATM in primary prostate cancer, although it is to be noted that the frequency of DNA repair mutations in localized prostate cancer is low [108, 178, 179]. Interestingly, mutations in DNA repair enzymes (BRCA2, ATM, BRCA1, FANCA, RAD51B, RAD51C, MLH1, and MSH2) are the major disease-specific mutations in mCRPC [180, 181]. The understanding that a quarter of men with mCRPC have mutations in DNA repair pathway genes such as BRCA genes has led to clinical trials with poly ADP ribose polymerase (PARP) inhibitors. PARPs are required to repair the DNA single-strand breaks through base-excision repair. It has been shown that cancer cells with BRCA gene mutations become significantly more sensitive to PARP inhibitors as a therapeutic approach popularly known as synthetic lethal strategy [180, 181]. It is further noted that mutations of other DNA repair pathway genes can be sensitive to PARP inhibitors. These genes are ATM, BRIP1, BARD1, CDK12, CHEK2, FANCA, NBN, PALB2, and RAD51 [182, 183].
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In addition to their use in cancer therapy, PARP inhibitors appear to produce some therapeutic benefit in other disease areas such as stroke, myocardial infarction, and neurodegenerative disorders, and the mechanisms of these effects are currently under investigation.
BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
PARP inhibitors are an exciting class of agents that have demonstrated efficacy in many different tumor types. There is a large body of data on the activity of PARP inhibitors as single agents in BRCA-mutated tumors via synthetic lethality. The most robust clinical data is in ovarian and breast cancers positive for BRCA-mutation. More recently, there have been promising results in prostate and pancreatic cancers as well, since a fraction of these tumors also harbor BRCA 1/2 mutations. Activity has also been demonstrated in high-grade serous ovarian cancer without BRCA mutations, presumably due to other defects in the DNA repair pathway. Three PARP inhibitors are now approved for clinical use as single agents in ovarian and/or breast cancer with BRCA mutations. Other agents in this class are in different stages of clinical development. Tumors with other defects in the HR pathway, including PTEN defects, Fanconi’s anemia protein defects, ATM abnormalities, RAD51 dysfunction, and EMSY defects, may also be sensitive to single agent PARP inhibitors through the process of synthetic lethality.
Anti-tumour and radiosensitising effects of PARP inhibitor on cervical cancer xenografts
Published in Journal of Obstetrics and Gynaecology, 2023
Qin Xue, Wang Enyang, Gong Tingting, Ma Xiaolin, Ma Qipeng, Gao Song
Since 1990, Begg (1990) proposed that the PARP inhibitors can replace cisplatin as radiosensitisers by avoiding the nephrotoxicity caused by cisplatin. In addition, most of the PARP inhibitors are oral drugs, which are convenient to use and non-invasive. Many of these inhibitors have shown antitumor activity and ameliorate the antitumor efficacy of cytotoxic DNA-damaging agents including both chemotherapy (such as alkylating agents, topoisomerase 1 and platinum) and ionising radiation. However, due to limited sample size and clinical data, most of the trials are in the exploratory stage. Besides, several in vivo models have confirmed the radiosensitisation of PARP inhibitors (Brock et al.2004, Calabrese et al.2004, Albert et al.2007, Senra et al.2011, Tuli et al.2014).
PARP inhibitors: clinical relevance and the role of multidisciplinary cancer teams on drug safety
Published in Expert Opinion on Drug Safety, 2022
Mafalda Jesus, Manuel Morgado, Ana Paula Duarte
Poly (ADP-Ribose) polymerases (PARP) are a superfamily of 18 proteins involved in processes from cell proliferation to cell death such as repairing DNA damage, apoptosis and transcription regulation [2–4]. In this context, over the last decade, the development of PARP inhibitors (PARPi) has emerged as a new target in cancer therapy. As a result, the U.S. Food and Drug Agency (FDA) and European Medicines Agency (EMA) have already approved four PARPi, namely: olaparib, rucaparib, niraparib and talazoparib. The approved clinical indications for these drugs focus particularly on the treatment of ovarian, breast, pancreas and prostate cancer [5–8]. In addition, other PARPi are under investigation. In addition, other PARPi are under investigation. Veliparib and pamiparib have not yet been approved by drug regulatory agencies. PARPi are also emerging as new therapeutic options for other types of cancer. PARPi alone or in combination with other therapeutic agents are being investigated in several ongoing phase I/II/III clinical trials for the treatment of metastatic urothelial carcinoma [9].
Risk of fatigue with PARP inhibitors in cancer patients: a systematic review and meta-analysis of 29 phase II/III randomized controlled trials
Published in Journal of Chemotherapy, 2021
The development of PARP inhibitors has opened up a new array of effective and relatively safe drugs for the treatment of patients with ovarian cancer, breast cancer, and other types of cancers. The five PARP inhibitors evaluated within our analysis are olaparib, rucaparib, niraparib, talazoparib, and veliparib. Olaparib and rucaparib were approved by FDA for treatment of patients with deleterious BRCA mutation advanced ovarian cancer who have received two or more chemotherapy regimens. Niraparib was approved by FDA in 2017 for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In 2018, talazoparib was approved by FDA for treating patients with deleterious or suspected deleterious germline BRCA-mutated, HER2‐negative locally advanced or metastatic breast cancer. However, combining PARP inhibitors with chemotherapy has been challenging because of toxic effects that result in substantial dose reductions.19 Veliparib is an oral PARP inhibitor that has shown activity as a single agent in early-phase trials and that can be combined with standard chemotherapy doses.28,38,39 A number of ongoing phase II and III studies28,32,37 are assessing the efficacy and toxicity of veliparib in solid tumors, thus veliparib was also included in our study.