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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].
The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Another aspect of BRCA1 is that it can be used in a prognostic manner to predict a patient’s response to chemotherapy. For example, BRCA1 plays an important role in stimulating the repair of damaged DNA in cells. Thus, a mutation in the BRCA gene can cause hypersensitivity to DNA-damaging chemotherapeutic agents. In particular, BRCA1 mutations can make tumor cells significantly more sensitive to PARP inhibition, increasing the rate of apoptosis. This has been used as a biomarker to select patients for treatment with PARP inhibitors such as olaparib (LynparzaTM). Conversely, BRCA1 mutations can influence the outcome of treatment with antitubulin agents such as the taxanes (e.g., paclitaxel) and the vinca alkaloids (e.g., vinblastine) causing resistance to these therapies.
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
PARPs are a family of proteins with enzymatic properties, scaffolding properties, and recruiting abilities for other necessary DNA repair proteins. PARP affects repair for SSBs, primarily as part of BER [131]. PARP 1 and PARP 2 are the best studied of these proteins and the targets of most of the PARP inhibitors currently under development for cancer therapy [34]. PARP proteins were initially identified in 1963 [108], and in 1980 it was proposed that they enhance alkylator activity [30]. In response to DNA damage, PARP produces PAR and transfers it to acceptor proteins on the PARP itself and other proteins involved in DNA repair. The negative charge of PAR causes PARP 1 to lose its affinity for DNA. PAR then recruits other repair proteins to the damaged DNA site (Fig. 15.1). PAR also binds XRCC1, the scaffolding protein. PARP 1 retains the largest amount of PAR. PAR regulates histone H1 binding to chromatin, allowing the chromatin to relax. PARP is involved in methylation and transcription of genes coding for cell cycle and stress response, including p53. PAR attaches DNA polymerase ß to the DNA break site to replace the missing bases. Finally, PAR combines with DNA ligase III to seal the DNA [25, 108, 113].
The effect of PARP inhibitors in homologous recombination proficient ovarian cancer: meta-analysis
Published in Journal of Chemotherapy, 2023
Marko Skelin, David Šarčević, Dina Lešin Gaćina, Iva Mucalo, Ivo Dilber, Eugen Javor
Interestingly, recent clinical evidence is showing that patients without BRCA mutations and HRD could benefit from PARP inhibitors treatment as well [10]. At the beginning of PARP-1 protein research, studies focused on its DNA repair mechanism. More recently, the focus has been broadened towards gene expression, ribosome biogenesis, RNA processing and chromatin structure regulation. Those recently discovered various roles of PARP-1 could explain the beneficial PARP inhibitors effect in patients without BRCA mutations and HRD [11]. A recent study demonstrated that PARP inhibitors treatment reduces ribosome biogenesis and cell growth through impaired nucleolar localization. These findings support the rationale to conduct clinical trials of PARP inhibitors in non BRCA mutated and HR proficient EOC patients [12,13].
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.
Recent development in the discovery of PARP inhibitors as anticancer agents: a patent update (2016-2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Uday Kiran Velagapudi, Bhargav A. Patel, Xuwei Shao, Sanjai Kumar Pathak, Dana V. Ferraris, Tanaji T. Talele
PARP1 was the first identified member of the family and remains as the most investigated enzyme, serving as the ‘guardian angel of the genome’ [7], while sharing a higstructural homology with PARP2 enzyme [8]. PARP1 is primarily (and to minor extent, PARP2) involved in the initiation of repair processes during the onset of single strand breaks in DNA; this is achieved by recruiting repair proteins to the damaged site [9]. Small-molecule inhibitors targeting PARP1 demonstrate enhanced tumor cytotoxicity, especially in populations bearing a defective homologous recombination repair (HRR) mechanism, a process defined as synthetic lethality [10,11]. Several PARP1/2 inhibitory agents show differences in binding mechanisms leading to varying degrees of catalytic inhibition. Additionally, some inhibitors are known to trap PARP1 enzyme on DNA breaks leading to toxic complexes that significantly increase the cytotoxic burden on tumor cells [12,13]. The currently marketed PARPi’s (olaparib, niraparib, rucaparib, and talazoparib) are used as single agents for the treatment of tumors harboring a defective HRR pathway, e.g. in breast cancer and ovarian cancer (Figure 1) [14–17]. Additionally, these FDA approved PARP inhibitors (PARPi’s) as well as several newly developed PARP inhibitor candidates are currently being evaluated in the clinic as single agents in the treatment of various cancers or in combination with chemotherapy or radiotherapy against several solid tumors [1,18].