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https://www.readbyqxmd.com/read/29664016/the-evolving-landscape-of-predictive-biomarkers-of-response-to-parp-inhibitors
#1
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...
April 16, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29650751/fda-approval-summary-niraparib-for-the-maintenance-treatment-of-patients-with-recurrent-ovarian-cancer-in-response-to-platinum-based-chemotherapy
#2
Gwynn Ison, Lynn J Howie, Laleh Amiri-Kordestani, Lijun Zhang, Shenghui Tang, Rajeshwari Sridhara, Vadryn Pierre, Rosane Charlab, Anuradha Ramamoorthy, Pengfei Song, Fang Li, Jingyu Yu, Wimolnut Manheng, Todd R Palmby, Soma Ghosh, Hisani N Horne, Eunice Y Lee, Reena Philip, Kaushalkumar Dave, Xiao Hong Chen, Sharon L Kelly, Kumar G Janoria, Anamitro Banerjee, Okponanabofa Eradiri, Jeannette Dinin, Kirsten B Goldberg, William F Pierce, Amna Ibrahim, Paul G Kluetz, Gideon M Blumenthal, Julia A Beaver, Richard Pazdur
The Food and Drug Administration approved niraparib, a poly ADP ribose polymerase (PARP) inhibitor, on March 27, 2017, for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Approval was based on data from the NOVA trial comparing niraparib with placebo in two independent cohorts, based on germline BRCA mutation status (gBRCAm vs. non-gBRCAm). Progression-free survival (PFS) in each cohort was the primary endpoint...
April 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29644491/update-on-parp-inhibitors-in-breast-cancer
#3
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/29620474/pharmacokinetic-drug-evaluation-of-niraparib-for-the-treatment-of-ovarian-cancer
#4
Teresa C Longoria, Krishnansu S Tewari
Ovarian cancer is a disease with a propensity to recur despite dramatic responses to initial treatment, which typically consists of a combination of cytoreductive surgery and platinum-based chemotherapy. A maintenance therapy, which may prevent or delay relapse while not negatively impacting quality of life, is critical to improving outcomes. Areas covered: This review discusses the pharmacologic properties, clinical efficacy, and safety profile of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy...
April 5, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29605737/rucaparib-an-emerging-parp-inhibitor-for-treatment-of-recurrent-ovarian-cancer
#5
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/29512470/parp-inhibitors-in-ovarian-cancer
#6
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/29423093/combination-of-a-hypomethylating-agent-and-inhibitors-of-parp-and-hdac-traps-parp1-and-dnmt1-to-chromatin-acetylates-dna-repair-proteins-down-regulates-nurd-and-induces-apoptosis-in-human-leukemia-and-lymphoma-cells
#7
Benigno C Valdez, Yang Li, David Murray, Yan Liu, Yago Nieto, Richard E Champlin, Borje S Andersson
Combination of drugs that target different aspects of aberrant cellular processes is an efficacious treatment for hematological malignancies. Hypomethylating agents (HMAs) and inhibitors of poly(ADP-ribose) polymerases (PARPis) and histone deacetylases (HDACis) are clinically active anti-tumor drugs. We hypothesized that their combination would be synergistically cytotoxic to leukemia and lymphoma cells. Exposure of AML and lymphoma cell lines to the combination of the PARPi niraparib (Npb), the HMA decitabine (DAC) and the HDACi romidepsin (Rom) or panobinostat (Pano) synergistically inhibited cell proliferation by up to 70% via activation of the ATM pathway, increased production of reactive oxygen species, decreased mitochondrial membrane potential, and activated apoptosis...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29405820/the-irreversible-erbb1-2-4-inhibitor-neratinib-interacts-with-the-parp1-inhibitor-niraparib-to-kill-ovarian-cancer-cells
#8
Laurence Booth, Jane L Roberts, Peter Samuel, Francesca Avogadri-Connors, Richard E Cutler, Alshad S Lalani, Andrew Poklepovic, Paul Dent
The irreversible ERBB1/2/4 inhibitor neratinib has been shown to rapidly down-regulate the expression of ERBB1/2/4 as well as the levels of c-MET, PDGFRα and mutant RAS proteins via autophagic degradation. Neratinib interacted in an additive to synergistic fashion with the approved PARP1 inhibitor niraparib to kill ovarian cancer cells. Neratinib and niraparib caused the ATM-dependent activation of AMPK which in turn was required to cause mTOR inactivation, ULK-1 activation and ATG13 phosphorylation. The drug combination initially increased autophagosome levels followed later by autolysosome levels...
February 6, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29397193/the-poly-adp-ribose-polymerase-inhibitor-niraparib-management-of-toxicities
#9
Kathleen N Moore, Mansoor Raza Mirza, Ursula A Matulonis
Niraparib is an oral poly(ADP ribose) polymerase (PARP) inhibitor that is currently approved by the United States Food and Drug Administration (US FDA) as well as recently approved by the European Medicines Agency (EMA) for the maintenance treatment of women with recurrent ovarian cancer who are in complete or partial response to platinum-based chemotherapy. The mechanisms of action of niraparib include inhibition of PARP enzymatic activity as well as increased formation of PARP-DNA complexes through "trapping" the PARP enzyme on damaged DNA...
January 31, 2018: Gynecologic Oncology
https://www.readbyqxmd.com/read/29327913/proteomic-analysis-of-the-downstream-signaling-network-of-parp1
#10
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/29322231/the-effect-of-food-on-the-pharmacokinetics-of-niraparib-a-poly-adp-ribose-polymerase-parp-inhibitor-in-patients-with-recurrent-ovarian-cancer
#11
Kathleen Moore, Zhi-Yi Zhang, Shefali Agarwal, Howard Burris, Manish R Patel, Vikram Kansra
PURPOSE: Niraparib is a highly selective inhibitor of PARP-1 and PARP-2 approved in the United States for maintenance treatment of adult patients with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy. In this open-label crossover study, we evaluated the effects of food on niraparib pharmacokinetics (PK) and safety. METHODS: Patients received a single 300-mg dose of niraparib either after a high-fat meal or under fasting conditions...
March 2018: Cancer Chemotherapy and Pharmacology
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
#12
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/29251678/novel-poly-adp-ribose-polymerase-inhibitor-combination-strategies-in-ovarian-cancer
#13
Kelly E McCann
PURPOSE OF REVIEW: The recent United States Food and Drug Administration approvals of niraparib and olaparib as maintenance monotherapy for platinum-sensitive, high-grade ovarian cancers independent of BRCA status reflect a willingness to seek indications for poly-ADP-ribose polymerase (PARP) inhibitors beyond cancers with deleterious breast cancer 1 and breast cancer 2 mutations. In this review, I describe the rationale behind current PARP combination clinical trials with chemotherapies, angiogenesis inhibitors, cell cycle checkpoint inhibitors, and inhibitors of the phosphoinositide 3-kinase/AK thymoma/mechanistic target of rapamycin pathway...
February 2018: Current Opinion in Obstetrics & Gynecology
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
#14
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/29181573/correction-to-determination-of-the-absolute-oral-bioavailability-of-niraparib-by-simultaneous-administration-of-a-14-c-microtracer-and-therapeutic-dose-in-cancer-patients
#15
L van Andel, H Rosing, Z Zhang, L Hughes, V Kansra, M Sanghvi, M M Tibben, A Gebretensae, J H M Schellens, J H Beijnen
The article ''Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a14 C-microtracer and therapeutic dose in cancer patients'', written by L. van Andel, H. Rosing, Z. Zhang, L. Hughes, V. Kansra, M. Sanghvi, M. M. Tibben, A. Gebretensae, J. H. M. Schellens and J. H. Beijnen, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 17th October 2017 without open access.
January 2018: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29180466/synthetic-lethality-of-parp-inhibitors-in-combination-with-myc-blockade-is-independent-of-brca-status-in-triple-negative-breast-cancer
#16
Jason P W Carey, Cansu Karakas, Tuyen Bui, Xian Chen, Smruthi Vijayaraghavan, Yang Zhao, Jing Wang, Keith Mikule, Jennifer K Litton, Kelly K Hunt, Khandan Keyomarsi
PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients. Several of those patients exhibit intrinsic/acquired resistance mechanisms that limit efficacy of PARPi monotherapy. Here we show how the efficacy of PARPi in triple-negative breast cancers (TNBC) can be expanded by targeting MYC-induced oncogenic addiction. In BRCA-mutant/sporadic TNBC patients, amplification of the MYC gene is correlated with increased expression of the homologous DNA recombination enzyme RAD51 and tumors overexpressing both genes are associated with worse overall survival...
February 1, 2018: Cancer Research
https://www.readbyqxmd.com/read/29138572/current-status-of-poly-adp-ribose-polymerase-inhibitors-and-future-directions
#17
REVIEW
Akihiro Ohmoto, Shinichi Yachida
Inhibitors of poly(ADP-ribose) polymerases (PARPs), which play a key role in DNA damage/repair pathways, have been developed as antitumor agents based on the concept of synthetic lethality. Synthetic lethality is the idea that cell death would be efficiently induced by simultaneous loss of function of plural key molecules, for example, by exposing tumor cells with inactivating gene mutation of BRCA-mediated DNA repair to chemically induced inhibition of PARPs. Indeed, three PARP inhibitors, olaparib, rucaparib and niraparib have already been approved in the US or Europe, mainly for the treatment of BRCA -mutant ovarian cancer...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29081841/niraparib-in-ovarian-cancer-results-to-date-and-clinical-potential
#18
REVIEW
Davide Caruso, Anselmo Papa, Silverio Tomao, Patrizia Vici, Pierluigi Benedetti Panici, Federica Tomao
Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2 , two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA -mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy...
September 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/29075104/risk-of-severe-hematologic-toxicities-in-cancer-patients-treated-with-parp-inhibitors-a-meta-analysis-of-randomized-controlled-trials
#19
Jian Xin Zhou, Li Jin Feng, Xi Zhang
PURPOSE: Hematologic toxicities, including neutropenia, thrombocytopenia, and anemia, are major adverse effects of PARP inhibitors (PARPis), but the incidence rate and overall risk has not been systematically studied. Therefore, we conducted a meta-analysis of published clinical trials to investigate the incidence and relative risks (RRs) of severe (high-grade) hematologic events in cancer patients treated with PARPis. METHODS: PubMed, Embase, and oncology conference proceedings were searched for relevant studies...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29043410/determination-of-the-absolute-oral-bioavailability-of-niraparib-by-simultaneous-administration-of-a-14-c-microtracer-and-therapeutic-dose-in-cancer-patients
#20
L van Andel, H Rosing, Z Zhang, L Hughes, V Kansra, M Sanghvi, M M Tibben, A Gebretensae, J H M Schellens, J H Beijnen
INTRODUCTION: Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo...
January 2018: Cancer Chemotherapy and Pharmacology
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