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https://www.readbyqxmd.com/read/29750420/latest-clinical-evidence-and-further-development-of-parp-inhibitors-in-ovarian-cancer
#1
M R Mirza, S Pignata, J A Ledermann
Background: For several decades, the systemic treatment of ovarian cancer has involved chemotherapy, with the relatively recent addition of anti-angiogenic strategies given with chemotherapy and in the maintenance setting. In the past decade, numerous poly(ADP-ribose) polymerase (PARP)-inhibiting agents have been assessed. Design: We review key trials that have led to the approval of three PARP inhibitors - olaparib, niraparib and rucaparib - as maintenance therapy for platinum-sensitive recurrent ovarian cancer...
May 10, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29672168/rucaparib-a-new-treatment-option-for-ovarian-cancer
#2
Ilaria Sabatucci, Giuseppa Maltese, Stefano Lepori, Elisa Tripodi, Giorgio Bogani, Domenica Lorusso
Approximately 50% of high-grade serous ovarian cancers present a deficiency in the pathways involved in homologous recombination (HR). PARP inhibitors prevent single-strand DNA damage repair and determine a progression of the defect towards double-strand breaks, which results in a process known as 'synthetic lethality'. Areas covered: In this review, the authors discuss the efficacy and toxicity of rucaparib either as a single agent or as a maintenance treatment for ovarian cancer. This includes the NGS Foundation Medicine evaluation of the role of this drug in the treatment algorithm of ovarian cancer...
April 19, 2018: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/29664016/the-evolving-landscape-of-predictive-biomarkers-of-response-to-parp-inhibitors
#3
Anish Thomas, Junko Murai, Yves Pommier
Poly(ADP-ribose) polymerase inhibitors (PARPis) are DNA-damaging agents that trap PARP-DNA complexes and interfere with DNA replication. Three PARPis - olaparib, niraparib, and rucaparib - were recently approved by the FDA for the treatment of breast and ovarian cancers. These PARPis, along with 2 others (talazoparib and veliparib), are being evaluated for their potential to treat additional malignancies, including prostate cancers. While lack of PARP-1 confers high resistance to PARPis, it has not been established whether or not the levels of PARP-1 directly correlate with tumor response...
May 1, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29644491/update-on-parp-inhibitors-in-breast-cancer
#4
REVIEW
Alexandra S Zimmer, Mitchell Gillard, Stanley Lipkowitz, Jung-Min Lee
The single agent activity of PARP inhibitors (PARPi) in germline BRCA mutated (gBRCAm) breast and ovarian cancer suggests untapped potential for this new class of drug in breast cancer. The US Food and Drug Administration has approved three PARPi (olaparib, rucaparib, and niraparib) so far to treat certain ovarian cancers, including those with gBRCAm and olaparib for treatment of gBRCAm breast cancers. Several PARPi are now under clinical development for breast cancer in the various treatment settings. Recently, two phase III trials of olaparib (OlympiaD) and talazoparib (EMBRACA) demonstrated 3-month progression-free survival improvement with PARPi compared to physician's choice single agent chemotherapy in metastatic gBRCAm breast cancer...
April 11, 2018: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/29606854/rucaparib-a-novel-parp-inhibitor-for-brca-advanced-ovarian-cancer
#5
REVIEW
Ilaria Colombo, Stephanie Lheureux, Amit Manulal Oza
Rucaparib is a potent small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) proteins (PARP-1, PARP-2 and PARP-3) that play an important role in repairing DNA damage and maintaining genomic stability. Tumors with mutations in BRCA1/2 or other homologous recombination deficiency (HRD) genes are particularly sensitive to PARP inhibitors because of "synthetic lethality", whereby a therapeutic agent can take advantage of an intrinsic weakness in DNA repair. Rucaparib has been investigated in several preclinical and clinical studies showing promising activity in BRCA -mutant and BRCA -wild-type epithelial ovarian cancers (EOCs)...
2018: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29605737/rucaparib-an-emerging-parp-inhibitor-for-treatment-of-recurrent-ovarian-cancer
#6
REVIEW
Angela Musella, Erlisa Bardhi, Claudia Marchetti, Laura Vertechy, Giusy Santangelo, Carolina Sassu, Federica Tomao, Francesco Rech, Renzo D'Amelio, Marco Monti, Innocenza Palaia, Ludovico Muzii, Pierluigi Benedetti Panici
Recently, Poly-ADP-Ribose Polymerase (PARP) inhibitors are one of the most intensively studied group of antiblastic agents for the management of recurrent ovarian cancer. Among this family, Olaparib was the first to be approved by European Medicines Agency as maintenance therapy post-response to platinum-based chemotherapy for recurrent ovarian cancer in women with deleterious BRCA1/2 mutation. Following that, the Food and Drug Administration (FDA) approved Olaparib monotherapy as fourth or later line of treatment in advanced ovarian cancer with deleterious germ-line BRCA1/2 mutation...
March 23, 2018: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29572258/direct-imaging-of-drug-distribution-and-target-engagement-of-the-parp-inhibitor-rucaparib
#7
Susanne Kossatz, Brandon Carney, Christoper Farley, Charles M Drain, Wolfgang A Weber, Thomas Reiner
PARP inhibitors have emerged as potent anti-tumor drugs. Here, we describe the intrinsic fluorescence properties of the FDA approved PARP inhibitor rucaparib and its potential to directly measure drug distribution and target engagement - a critical factor for understanding drug action and improving efficacy. Methods: We characterized the photophysical properties of rucaparib and determined its quantum yield and lifetime. Using confocal microscopy and flow cytometry, we imaged the intracellular distribution of rucaparib and measured uptake and release kinetics...
March 23, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/29567272/the-bet-inhibitor-incb054329-reduces-homologous-recombination-efficiency-and-augments-parp-inhibitor-activity-in-ovarian-cancer
#8
Andrew J Wilson, Matthew Stubbs, Phillip Liu, Bruce Ruggeri, Dineo Khabele
OBJECTIVE: Homologous recombination (HR)-proficient ovarian tumors have poorer clinical outcomes and show resistance to poly ADP ribose polymerase inhibitors (PARPi). A subset of HR-proficient ovarian tumors show amplification in bromodomain and extra-terminal (BET) genes such as BRD4. We aimed to test the hypothesis that BRD4 inhibition sensitizes ovarian cancer cells to PARPi by reducing HR efficiency and increasing DNA damage. METHODS: HR-proficient ovarian cancer cell lines (OVCAR-3, OVCAR-4, SKOV-3, UWB1...
March 20, 2018: Gynecologic Oncology
https://www.readbyqxmd.com/read/29550682/bioanalytical-assay-for-the-quantification-of-the-alk-inhibitor-lorlatinib-in-mouse-plasma-using-liquid-chromatography-tandem-mass-spectrometry
#9
Claudia Spatari, Wenlong Li, Alfred H Schinkel, Gaetano Ragno, Jan H M Schellens, Jos H Beijnen, Rolf W Sparidans
A bio-analytical assay for the first third generation ALK inhibitor lorlatinib in mouse plasma was developed and validated. Ten-μl plasma samples were prepared by adding rucaparib as the internal standard and precipitation of the plasma proteins. For LC-MS/MS analysis, compounds were eluted at 0.5 mL/min and separated on a 3-μm particle-size, polar embedded octadecyl silica column by gradient elution using 0.1% of formic acid (in water) and methanol. Compounds were monitored with positive electrospray ionization using a triple quadrupole mass spectrometer in selected reaction monitoring mode...
April 15, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29545475/olaparib-induced-adaptive-response-is-disrupted-by-foxm1-targeting-that-enhances-sensitivity-to-parp-inhibition
#10
Pingping Fang, Jill A Madden, Lisa Neums, Ryan K Moulder, M Laird Forrest, Jeremy Chien
FOXM1 transcription factor network is activated in over 84% of cases in high-grade serous ovarian cancer (HGSOC), and FOXM1 upregulates the expression of genes involved in the homologous recombination (HR) DNA damage and repair (DDR) pathway. However, the role of FOXM1 in PARP inhibitor response has not yet been studied. This study demonstrates that PARP inhibitor (PARPi), olaparib, induces the expression and nuclear localization of FOXM1. On the basis of ChIP-qPCR, olaparib enhances the binding of FOXM1 to genes involved in HR repair...
March 15, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29544053/poly-adp-ribose-polymerase-in-neurodegeneration-radiosynthesis-and-radioligand-binding-in-arc-swe-tg-mice
#11
Santosh R Alluri, Patrick J Riss
We report the synthesis, radiosynthesis, and characterization of a radioligand for poly(ADP-ribose) polymerase (PARP). PARP is of central importance in cell homeostasis, neuroplasticity, and neurodegeneration in the brain. A radiolabeled PARP inhibitor was developed and used for autoradiographic quantification of PARP protein concentration in wild-type and transgenic rodent brains ex vivo in high resolution. The binding of [3 H]rucaparib was found to be confined to PARP-expressing domains, for example, cerebellar cortex or hippocampal regions in both models...
March 16, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29512470/parp-inhibitors-in-ovarian-cancer
#12
Gloria Mittica, Eleonora Ghisoni, Gaia Giannone, Sofia Genta, Massimo Aglietta, Anna Sapino, Giorgio Valabrega
BACKGROUND: Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. OBJECTIVES: To highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis...
March 5, 2018: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/29456106/design-synthesis-and-anticancer-activities-evaluation-of-novel-5h-dibenzo-b-e-azepine-6-11-dione-derivatives-containing-1-3-4-oxadiazole-units
#13
Xin He, Xin-Yang Li, Jing-Wei Liang, Chong Cao, Shuai Li, Ting-Jian Zhang, Fan-Hao Meng
Rucaparib and PJ34 were used as the structural model for the design of novel 5H-dibenzo[b,e]azepine-6,11-dione derivatives containing 1,3,4-oxadiazole units. And target compounds were successfully synthesized through a 3-step synthetic strategy. All target compounds were screened for their anti-proliferative effects against OVCAR-3 cell line. Preliminary biological study of these compounds provided potent compounds d21 and d22 with better activities than Rucaparib.
March 1, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29393407/parp1-sirna-suppresses-human-prostate-cancer-cell-growth-and-progression
#14
Yongchang Lai, Zhenzhen Kong, Tao Zeng, Shaohong Xu, Xiaolu Duan, Shujue Li, Chao Cai, Zhijian Zhao, Wenqi Wu
Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib or rucaparib, have shown treatment efficacy in BRCA1/2-deficient tumors. However, since PARP inhibitors (PARPi) mainly modulate the activation of PARP but not its expression, whether small interfering RNA (siRNA) specific to PARP has the same function as PARPi has not been well defined. In the present study it was demonstrated that PARP1-siRNA could reduce prostate cancer (PCa) cell progression regardless of the BRCA1/2 mutation. PARP1 silencing could significantly inhibit PC3 cell migration and invasion...
April 2018: Oncology Reports
https://www.readbyqxmd.com/read/29371919/sensitizing-ewing-sarcoma-to-chemo-and-radiotherapy-by-inhibition-of-the-dna-repair-enzymes-dna-protein-kinase-dna-pk-and-poly-adp-ribose-polymerase-parp-1-2
#15
Britta Vormoor, Yvonne T Schlosser, Helen Blair, Abhishek Sharma, Sarah Wilkinson, David R Newell, Nicola Curtin
Background: DNA-PK and PARP inhibitors sensitize cancer cells to chemo- and radiotherapy. ETS transcription factors (EWS-FLI1) have been described as biomarkers for PARP-inhibitor sensitivity. Sensitivity to single agent PARP inhibitors has so far been limited to homologous recombination repair (HRR) deficient tumors, exploiting synthetic lethality. Results: In clonogenic assays, single agent rucaparib LD50 values for continuously exposed cells were similar to those observed in HRR-defective cells (CAPAN-1 cell line, BRCA2 defective); however, both ES cell lines (TC-71, CADO-ES1) had functional HRR...
December 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/29327913/proteomic-analysis-of-the-downstream-signaling-network-of-parp1
#16
Yuanli Zhen, Yonghao Yu
Poly-ADP-ribosylation (PARylation) is a protein posttranslational modification (PTM) that is critically involved in many biological processes that are linked to cell stress responses. It is catalyzed by a class of enzymes known as poly-ADP-ribose polymerases (PARPs). In particular, PARP1 is a nuclear protein that is activated upon sensing nicked DNA. Once activated, PARP1 is responsible for the synthesis of a large number of PARylated proteins and initiation of the DNA damage response mechanisms. This observation provided the rationale for developing PARP1 inhibitors for the treatment of human malignancies...
January 30, 2018: Biochemistry
https://www.readbyqxmd.com/read/29274141/acquired-resistance-of-phosphatase-and-tensin-homolog-deficient-cells-to-poly-adp-ribose-polymerase-inhibitor-and-ara-c-mediated-by-53bp1-loss-and-samhd1-overexpression
#17
Yu-Ting Wang, Bo Yuan, Hua-Dong Chen, Lin Xu, Yu-Nan Tian, Ao Zhang, Jin-Xue He, Ze-Hong Miao
With increasing uses of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the phosphatase and tensin homolog (PTEN)-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46-71.78-fold) to all 5 PARPi, including niraparib and rucaparib, and showed higher degrees of resistance to the PARPi to which the parental cells were more sensitive...
March 2018: Cancer Science
https://www.readbyqxmd.com/read/29214031/parp-inhibitors-as-potential-therapeutic-agents-for-various-cancers-focus-on-niraparib-and-its-first-global-approval-for-maintenance-therapy-of-gynecologic-cancers
#18
REVIEW
Mekonnen Sisay, Dumessa Edessa
Poly (ADP-ribose) polymerases (PARPs) are an important family of nucleoproteins highly implicated in DNA damage repair. Among the PARP families, the most studied are PARP1, PARP2 and PARP 3. PARP1 is found to be the most abundant nuclear enzyme under the PARP series. These enzymes are primarily involved in base excision repair as one of the major single strand break (SSB) repair mechanisms. Being double stranded, DNA engages itself in reparation of a sub-lethal SSB with the aid of PARP. Moreover, by having a sister chromatid, DNA can also repair double strand breaks with either error-free homologous recombination or error-prone non-homologous end-joining...
2017: Gynecologic Oncology Research and Practice
https://www.readbyqxmd.com/read/29189915/targeting-brca1-2-deficient-ovarian-cancer-with-cndac-based-drug-combinations
#19
Xiaojun Liu, Yingjun Jiang, Billie Nowak, Bethany Qiang, Nancy Cheng, Yuling Chen, William Plunkett
PURPOSE: The mechanism of action of CNDAC (2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosyl-cytosine) is unique among deoxycytidine analogs because upon incorporation into DNA it causes a single strand break which is converted to a double strand break after DNA replication. This lesion requires homologous recombination (HR) for repair. CNDAC, as the parent nucleoside, DFP10917, and as an oral prodrug, sapacitabine, are undergoing clinical trials for hematological malignancies and solid tumors...
February 2018: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29166829/rucaparib-a-poly-adp-ribose-polymerase-inhibitor-for-brca-mutated-relapsed-ovarian-cancer
#20
Donald C Moore, J Tanner Ringley, Jolly Patel
OBJECTIVE: To review the pharmacology, safety, efficacy, and the role of rucaparib in the treatment of relapsed, advanced ovarian cancer. SUMMARY: A total of 2 phase I/II trials and 1 phase II trial have evaluated the safety and efficacy of oral rucaparib in ovarian cancer. In patients with deleterious BRCA1/2 mutation, an overall response rate of 80% was achieved in the phase II trial Assessment of Rucaparib in Ovarian CancEr Trial 2 (ARIEL2). In the same trial, progression-free survival was higher in patients with BRCA1/2 mutation and BRCA wild types with high loss of heterozygosity (LOH) than BRCA wild types with low LOH...
January 1, 2017: Journal of Pharmacy Practice
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