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https://www.readbyqxmd.com/read/29274141/acquired-resistance-of-pten-deficient-cells-to-parp-inhibitor-and-ara-c-mediated-by-53bp1-loss-and-samhd1-overexpression
#1
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 PARP inhibitors (PARPis) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the 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 PARPis including niraparib and rucaparib and showed higher degrees of resistance to the PARPis to which the parental cells were more sensitive...
December 22, 2017: Cancer Science
https://www.readbyqxmd.com/read/29260919/the-development-of-parp-as-a-successful-target-for-cancer-therapy
#2
Roberto Ferrara, Francesca Simionato, Chiara Ciccarese, Elisabetta Grego, Sara Cingarlini, Roberto Iacovelli, Emilio Bria, Giampaolo Tortora, Davide Melisi
PARP1 and BRCA genes are essential genome caretakers and their interaction has been the first example of synthetic lethality, a genetic concept proposed in the early 20th century, but deeply explored in cancer patients only in the last decade. Areas covered: This review describes PARP1 and BRCA main functions and different roles in genome protection. Furthermore, an overview of the principle mechanisms of action and resistance to PARP inhibitors (PARPi) is presented. This review illustrates the concept of BRCAness, and how this discovery has broadened the routes of PARPi to several different malignancies such as ovarian, breast and prostate cancer...
December 20, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29248130/guidance-statement-on-brca1-2-tumor-testing-in-ovarian-cancer-patients
#3
REVIEW
Ettore Capoluongo, Gillian Ellison, José Antonio López-Guerrero, Frederique Penault-Llorca, Marjolijn J L Ligtenberg, Susana Banerjee, Christian Singer, Eitan Friedman, Birgid Markiefka, Peter Schirmacher, Reinhard Büttner, Christi J van Asperen, Isabelle Ray-Coquard, Volker Endris, Suzanne Kamel-Reid, Natalie Percival, Jane Bryce, Benno Röthlisberger, Richie Soong, David Gonzalez de Castro
The approval, in 2015, of the first poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib, Lynparza) for platinum-sensitive relapsed high-grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast or ovarian cancer...
June 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/29232465/new-treatments-in-ovarian-cancer
#4
E Pujade-Lauraine
In targeting DNA repair pathways of the most genomic instable cancer, poly-(adenosine diphosphate [ADP])-ribose polymerase inhibitors (PARPi) have been demonstrated as the most effective drug since platinum in high grade serous or endometrioid ovarian cancer. Immunotherapy is strongly pushing the door of ovarian cancer and has the ambition to change the fate of this deadly disease when combined with chemotherapy, vascular endothelial growth factor inhibitor or PARPi. The activity of PARPi could also be improved by modulators of the cell cycle, which are required to give time enough for DNA repair...
November 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29223478/phase-ii-trial-of-veliparib-in-patients-with-previously-treated-brca-mutated-pancreas-ductal-adenocarcinoma
#5
Maeve A Lowery, David P Kelsen, Marinela Capanu, Sloane C Smith, Jonathan W Lee, Zsofia K Stadler, Malcolm J Moore, Hedy L Kindler, Talia Golan, Amiel Segal, Hannah Maynard, Ellen Hollywood, MaryEllen Moynahan, Erin E Salo-Mullen, Richard Kinh Gian Do, Alice P Chen, Kenneth H Yu, Laura H Tang, Eileen M O'Reilly
PURPOSE: BRCA-associated cancers have increased sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPis). This single arm, non-randomised, multicentre phase II trial evaluated the response rate of veliparib in patients with previously treated BRCA1/2- or PALB2-mutant pancreatic adenocarcinoma (PDAC). METHODS: Patients with stage III/IV PDAC and known germline BRCA1/2 or PALB2 mutation, 1-2 lines of treatment, Eastern Cooperative Oncology Group 0-2, were enrolled...
December 7, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29190394/acetylation-of-53bp1-dictates-the-dna-double-strand-break-repair-pathway
#6
Xiang Guo, Yongtai Bai, Meimei Zhao, Mei Zhou, Qinjian Shen, Cai-Hong Yun, Hongquan Zhang, Wei-Guo Zhu, Jiadong Wang
P53-binding protein 1 (53BP1) plays critical roles in DNA double strand break (DSB) repair by promoting non-homologous end joining (NHEJ), and loss of 53BP1 abolishes PARPi sensitivity in BRCA1-deficient cells by restoring homologous recombination (HR). 53BP1 is one of the proteins initially recruited to sites of DSBs via recognition of H4K20me2 through the Tudor-UDR domain and H2AK15ub through the UDR motif. Although extensive studies have been conducted, it remains unclear how the post-translational modification of 53BP1 affects DSB repair pathway choice...
November 28, 2017: Nucleic Acids Research
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
#7
Jason Pw 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...
November 27, 2017: Cancer Research
https://www.readbyqxmd.com/read/29156666/betting-on-combination-to-overcome-parpi-resistance
#8
EDITORIAL
Youyou Zhang, Chi V Dang, Lin Zhang
No abstract text is available yet for this article.
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29152062/rapamycin-sensitizes-cancer-cells-to-growth-inhibition-by-the-parp-inhibitor-olaparib
#9
Atsushi Osoegawa, Joell J Gills, Shigeru Kawabata, Phillip A Dennis
Poly (ADP-ribose) polymerase inhibitors (PARPi) have been developed and tested in a context of combining it with double-stranded (ds) DNA repair defects or inhibitors, as PARP inhibitor impairs single-stranded (ss) DNA break repair, resulting in the activation of the dsDNA break repair machinery. Rapamycin has been widely prescribed for more than a decade and recent studies have revealed that it may inhibit dsDNA break repair. The combination of the PARP inhibitor olaparib and rapamycin synergistically inhibited cell proliferation in non-small cell lung cancer (NSCLC) cells, and even in triple negative breast cancer (TNBC) cells with BRCA1 mutations...
October 20, 2017: Oncotarget
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
#10
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/29054544/-abnormalities-of-dna-repair-and-gynecological-cancers
#11
REVIEW
Aurélie Auguste, Alexandra Leary
The demonstration of frequent defects in the DNA damage response in high grade ovarian cancer has paved the way for a new therapeutic approach aimed at exploiting this unique vulnerability. The efficacy of poly (ADP) ribose polymerase inhibitors (PARPi) in patients with homologous recombination (HR) DNA repair deficient ovarian cancer (OC) resulting from a BRCA1/2 mutation has provided the proof of concept for synthetic lethality. Thus, olaparib is now approved by the EMA as maintenance therapy after response to a platinum regimen for patients with recurrent, platinum-sensitive, high-grade serous, BRCA1/2-mutated ovarian cancer...
October 17, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29035360/ezh2-promotes-degradation-of-stalled-replication-forks-by-recruiting-mus81-through-histone-h3-trimethylation
#12
Beatrice Rondinelli, Ewa Gogola, Hatice Yücel, Alexandra A Duarte, Marieke van de Ven, Roxanne van der Sluijs, Panagiotis A Konstantinopoulos, Jos Jonkers, Raphaël Ceccaldi, Sven Rottenberg, Alan D D'Andrea
The emergence of resistance to poly-ADP-ribose polymerase inhibitors (PARPi) poses a threat to the treatment of BRCA1 and BRCA2 (BRCA1/2)-deficient tumours. Stabilization of stalled DNA replication forks is a recently identified PARPi-resistance mechanism that promotes genomic stability in BRCA1/2-deficient cancers. Dissecting the molecular pathways controlling genomic stability at stalled forks is critical. Here we show that EZH2 localizes at stalled forks where it methylates Lys27 on histone 3 (H3K27me3), mediating recruitment of the MUS81 nuclease...
November 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28974545/the-hrd-decision-which-parp-inhibitor-to-use-for-whom-and-when
#13
Elise C Kohn, Jung-Min Lee, S Percy Ivy
Rucaparib, a polyADPribose polymerase inhibitor (PARPi), was approved recently for use in women with high-grade serous ovarian cancer (HGSOC). It is now one of three approved PARPi for use in recurrent ovarian cancer, a family of agents that has changed the HGSOC treatment landscape and outcome. Clin Cancer Res; 23(23); 7155-7. ©2017 AACRSee related article by Balasubramaniam et al., p. 7165.
December 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28973445/redundancy-between-nucleases-required-for-homologous-recombination-promotes-parp-inhibitor-resistance-in-the-eukaryotic-model-organism-dictyostelium
#14
Anna-Lena Kolb, Alasdair R Gunn, Nicholas D Lakin
ADP-ribosyltransferases promote repair of DNA single strand breaks and disruption of this pathway by Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) is toxic to cells with defects in homologous recombination (HR). Here, we show that this relationship is conserved in the simple eukaryote Dictyostelium and exploit this organism to define mechanisms that drive resistance of the HR-deficient cells to PARPi. Dictyostelium cells disrupted in exonuclease I, a critical factor for HR, are sensitive to PARPi. Deletion of exo1 prevents the accumulation of Rad51 in chromatin induced by PARPi, resulting in DNA damage being channelled through repair by non-homologous end-joining (NHEJ)...
September 29, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28950147/genomic-signatures-as-predictive-biomarkers-of-homologous-recombination-deficiency-in-ovarian-cancer
#15
Adriaan Vanderstichele, Pieter Busschaert, Siel Olbrecht, Diether Lambrechts, Ignace Vergote
DNA repair deficiency is a common hallmark of many cancers and is increasingly recognised as a target for cancer therapeutics. Selecting patients for these treatments requires a functional assessment of multiple redundant DNA repair pathways. With the advent of whole-genome sequencing of cancer genomes, it is increasingly recognised that multiple signatures of mutational and chromosomal alterations can be correlated with specific DNA repair defects. The clinical relevance of this approach is underlined by the use of poly-(ADP-ribose) polymerase inhibitors (PARPi) in homologous recombination (HR) deficient high-grade serous ovarian cancers...
September 23, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28948212/dna-repair-deficiency-biomarkers-and-the-70-gene-ultra-high-risk-signature-as-predictors-of-veliparib-carboplatin-response-in-the-i-spy-2-breast-cancer-trial
#16
Denise M Wolf, Christina Yau, Ashish Sanil, Annuska Glas, Emanuel Petricoin, Julia Wulfkuhle, Tesa M Severson, Sabine Linn, Lamorna Brown-Swigart, Gillian Hirst, Meredith Buxton, Angela DeMichele, Nola Hylton, Fraser Symmans, Doug Yee, Melissa Paoloni, Laura Esserman, Don Berry, Hope Rugo, Olufunmilayo Olopade, Laura van 't Veer
Veliparib combined with carboplatin (VC) was an experimental regimen evaluated in the biomarker-rich neoadjuvant I-SPY 2 trial for breast cancer. VC showed improved efficacy in the triple negative signature. However, not all triple negative patients achieved pathologic complete response and some HR+HER2- patients responded. Pre-specified analysis of five DNA repair deficiency biomarkers (BRCA1/2 germline mutation; PARPi-7, BRCA1ness, and CIN70 expression signatures; and PARP1 protein) was performed on 116 HER2- patients (VC: 72 and concurrent controls: 44)...
2017: NPJ Breast Cancer
https://www.readbyqxmd.com/read/28925391/ezh2-contributes-to-the-response-to-parp-inhibitors-through-its-parp-mediated-poly-adp-ribosylation-in-breast-cancer
#17
H Yamaguchi, Y Du, K Nakai, M Ding, S-S Chang, J L Hsu, J Yao, Y Wei, L Nie, S Jiao, W-C Chang, C-H Chen, Y Yu, G N Hortobagyi, M-C Hung
Inhibitors against poly (ADP-ribose) polymerase (PARP) are promising targeted agents currently used to treat BRCA-mutant ovarian cancer and are in clinical trials for other cancer types, including BRCA-mutant breast cancer. To enhance the clinical response to PARP inhibitors (PARPis), understanding the mechanisms underlying PARPi sensitivity is urgently needed. Here, we show enhancer of zeste homolog 2 (EZH2), an enzyme that catalyzes H3 lysine trimethylation and associates with oncogenic function, contributes to PARPi sensitivity in breast cancer cells...
September 18, 2017: Oncogene
https://www.readbyqxmd.com/read/28893315/heterogeneous-drug-penetrance-of-veliparib-and-carboplatin-measured-in-triple-negative-breast-tumors
#18
Imke H Bartelink, Brendan Prideaux, Gregor Krings, Lisa Wilmes, Pei Rong Evelyn Lee, Pan Bo, Byron Hann, Jean-Philippe Coppé, Diane Heditsian, Lamorna Swigart-Brown, Ella F Jones, Sergey Magnitsky, Ron J Keizer, Niels de Vries, Hilde Rosing, Nela Pawlowska, Scott Thomas, Mallika Dhawan, Rahul Aggarwal, Pamela N Munster, Laura J Esserman, Weiming Ruan, Alan H B Wu, Douglas Yee, Véronique Dartois, Radojka M Savic, Denise M Wolf, Laura van 't Veer
BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples. METHODS: MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice...
September 11, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28886273/parpi-potentiates-with-current-conventional-therapy-in-mll-leukemia
#19
Lu Zhao, Chi Wai Eric So
Acute myeloid leukemias driven by MLL fusion proteins are commonly associated with poor prognosis and refractory treatment. Here, we provide evidence that olaparib can potentiate sensitivity of MLL leukemia cells to conventional chemotherapy and DNMT inhibitors offering new potential therapeutic strategies for MLL rearranged leukemias Using the primary mouse leukemia cells and human MLL-AF9 leukemic cell line, we demonstrate that treatment of MLL-AF9 leukemic cells with DNMT inhibitors or chemotherapies in combination with olaparib results in significant reduction in colony formation or cell growth while the single agent treatments had little impacts...
October 18, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28856922/detection-and-delineation-of-oral-cancer-with-a-parp1-targeted-optical-imaging-agent
#20
Susanne Kossatz, Wolfgang Weber, Thomas Reiner
More sensitive and specific methods for early detection are imperative to improve survival rates in oral cancer. However, oral cancer detection is still largely based on visual examination and histopathology of biopsy material, offering no molecular selectivity or spatial resolution. Intuitively, the addition of optical contrast could improve oral cancer detection and delineation, but so far no molecularly targeted approach has been translated. Our fluorescently labeled small-molecule inhibitor PARPi-FL binds to the DNA repair enzyme poly(ADP-ribose)polymerase 1 (PARP1) and is a potential diagnostic aid for oral cancer delineation...
January 2017: Molecular Imaging
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