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BRCA1 and BRCA2 and PARPi

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https://www.readbyqxmd.com/read/27498558/synthetic-viability-by-brca2-and-parp1-artd1-deficiencies
#1
Xia Ding, Arnab Ray Chaudhuri, Elsa Callen, Yan Pang, Kajal Biswas, Kimberly D Klarmann, Betty K Martin, Sandra Burkett, Linda Cleveland, Stacey Stauffer, Teresa Sullivan, Aashish Dewan, Hanna Marks, Anthony T Tubbs, Nancy Wong, Eugen Buehler, Keiko Akagi, Scott E Martin, Jonathan R Keller, André Nussenzweig, Shyam K Sharan
Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib has been approved for treatment of advanced ovarian cancer associated with BRCA1 and BRCA2 mutations. BRCA1- and BRCA2-mutated cells, which are homologous recombination (HR) deficient, are hypersensitive to PARPi through the mechanism of synthetic lethality. Here we examine the effect of PARPi on HR-proficient cells. Olaparib pretreatment, PARP1 knockdown or Parp1 heterozygosity of Brca2(cko/ko) mouse embryonic stem cells (mESCs), carrying a null (ko) and a conditional (cko) allele of Brca2, results in viable Brca2(ko/ko) cells...
August 8, 2016: Nature Communications
https://www.readbyqxmd.com/read/27428646/parp-inhibitors-in-clinical-use-induce-genomic-instability-in-normal-human-cells
#2
Shuhei Ito, Conleth G Murphy, Ekaterina Doubrovina, Maria Jasin, Mary Ellen Moynahan
Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA repair pathways to be targeted by specific inhibitors for clinical benefit. Tumors harboring genetic defects in homologous recombination (HR), a DNA double-strand break (DSB) repair pathway, are hypersensitive to PARP inhibitors (PARPi). Early phase clinical trials with PARPi have been promising in patients with advanced BRCA1 or BRCA2-associated breast, ovary and prostate cancer and have led to limited approval for treatment of BRCA-deficient ovary cancer...
2016: PloS One
https://www.readbyqxmd.com/read/27225819/brca1-2-diagnostic-workflow-from-next-generation-sequencing-technologies-to-variant-identification-and-final-report
#3
Brunella Pilato, Rosamaria Pinto, Simona De Summa, Daniela Petriella, Rosanna Lacalamita, Katia Danza, Angelo Paradiso, Stefania Tommasi
The BRCA1-BRCA2 genes predispose to hereditary breast and ovarian cancer, and the germline and mutational status of these genes defines a target population that can benefit from PARP inhibitor treatments. To respond to the increasing number of BRCA1-BRCA2 tests, it is necessary to shift to high-throughput technologies that are reliable and less time consuming. Different methodological platforms are dedicated to this purpose with different approaches and algorithms for analysis. Our aim was to set up a cost-effective and low time-consuming BRCA1-BRCA2 mutation detection workflow using the Ion Torrent PGM technology...
October 2016: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/26899229/cediranib-a-pan-vegfr-inhibitor-and-olaparib-a-parp-inhibitor-in-combination-therapy-for-high-grade-serous-ovarian-cancer
#4
S Percy Ivy, Joyce F Liu, Jung-Min Lee, Ursula A Matulonis, Elise C Kohn
INTRODUCTION: An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC)...
2016: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/26402249/pancreatic-cancer-brca-mutation-and-personalized-treatment
#5
REVIEW
Guopei Luo, Yu Lu, Kaizhou Jin, He Cheng, Meng Guo, Zuqiang Liu, Jiang Long, Chen Liu, Quanxing Ni, Xianjun Yu
The highly heterozygous nature of pancreatic cancer is partially responsible for its therapeutic ineffectiveness and resistance. Therefore, the ability to identify subgroups of pancreatic cancer with unique biological characteristics and treatment response is urgently needed. In addition to breast and ovarian cancer, pancreatic cancer is the third most common cancer type that is related to the early onset (BRCA) gene mutation in breast cancer. Mounting evidence has demonstrated that BRCA1/2-mutant breast and ovarian cancers are highly sensitive to DNA damage-related treatment, including poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum-based agents...
2015: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/25634215/a-unique-subset-of-epithelial-ovarian-cancers-with-platinum-sensitivity-and-parp-inhibitor-resistance
#6
Raphael Ceccaldi, Kevin W O'Connor, Kent W Mouw, Adam Y Li, Ursula A Matulonis, Alan D D'Andrea, Panagiotis A Konstantinopoulos
Platinum and PARP inhibitor (PARPi) sensitivity commonly coexist in epithelial ovarian cancer (EOC) due to the high prevalence of alterations in the homologous recombination (HR) DNA repair pathway that confer sensitivity to both drugs. In this report, we describe a unique subset of EOC with alterations in another DNA repair pathway, the nucleotide excision repair (NER) pathway, which may exhibit a discordance in sensitivities to these drugs. Specifically, 8% of high-grade serous EOC from The Cancer Genome Atlas dataset exhibited NER alterations, including nonsynonymous or splice site mutations and homozygous deletions of NER genes...
February 15, 2015: Cancer Research
https://www.readbyqxmd.com/read/25158060/evolution-of-pre-existing-versus-acquired-resistance-to-platinum-drugs-and-parp-inhibitors-in-brca-associated-cancers
#7
Kimiyo N Yamamoto, Kouji Hirota, Shunichi Takeda, Hiroshi Haeno
Platinum drugs and PARP inhibitors ("PARPis") are considered to be effective in BRCA-associated cancers with impaired DNA repair. These agents cause stalled and collapsed replication forks and create double-strand breaks effectively in the absence of repair mechanisms, resulting in arrest of the cell cycle and induction of cell death. However, recent studies have shown failure of these chemotherapeutic agents due to emerging drug resistance. In this study, we developed a stochastic model of BRCA-associated cancer progression in which there are four cancer populations: those with (i) functional BRCA, (ii) dysfunctional BRCA, (iii) functional BRCA and a growth advantage, and (iv) dysfunctional BRCA and a growth advantage...
2014: PloS One
https://www.readbyqxmd.com/read/25076338/parp-inhibitors-in-brca-associated-pancreatic-cancer
#8
Anshul Bhalla, Muhammad Wasif Saif
Recent data suggests that treating patients with pancreatic cancer that express mutations in BRCA1, BRCA2, and PALB2 with chemotherapy which targets the DNA repair defect in these cells, such as platinum based therapies or PARPi [poly (ADP-ribose) polymerase inhibitor], may be more beneficial in these patients. Moreover, further data also indicates the promise of combining PARPi with conventional chemotherapy. Authors summarize the data related to PARPi in BRCA-associated pancreatic cancer that was presented at the annual meeting of ASCO 2014...
July 2014: JOP: Journal of the Pancreas
https://www.readbyqxmd.com/read/25017803/poly-adp-ribose-polymerase-inhibitor-efficacy-in-head-and-neck-cancer
#9
Jana Heitmann, Paul Geeleher, Zhixiang Zuo, Ralph R Weichselbaum, Everett E Vokes, Sebastian Fetscher, Tanguy Y Seiwert
OBJECTIVES: Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown single agent activity against tumors with deficiencies in the DNA repair mechanism homologous recombination including, but not limited to those harboring BRCA mutations. We hypothesized that, in the context of homologous recombination deficiency (HRD), PARPi could have an effect in head and neck cancer (HNC). MATERIALS AND METHODS: We evaluated TCGA data for evidence of HRD using a copy number data signature established for breast cancer...
September 2014: Oral Oncology
https://www.readbyqxmd.com/read/24965603/quantitative-measurement-of-alterations-in-dna-damage-repair-ddr-pathways-using-single-cell-network-profiling-scnp
#10
David B Rosen, Ling Y Leung, Brent Louie, James A Cordeiro, Andrew Conroy, Iuliana Shapira, Scott Z Fields, Alessandra Cesano, Rachael E Hawtin
BACKGROUND: Homologous recombination repair (HRR) pathway deficiencies have significant implications for cancer predisposition and treatment strategies. Improved quantitative methods for functionally characterizing these deficiencies are required to accurately identify patients at risk of developing cancer and to identify mechanisms of drug resistance or sensitivity. METHODS: Flow cytometry-based single cell network profiling (SCNP) was used to measure drug-induced activation of DNA damage response (DDR) proteins in cell lines with defined HRR pathway mutations (including ATM-/-, ATM+/-, BRCA1+/-, BRCA2-/-) and in primary acute myeloid leukemia (AML) samples...
June 25, 2014: Journal of Translational Medicine
https://www.readbyqxmd.com/read/24842884/on-the-road-to-parpi-platin
#11
EDITORIAL
Michael A Bookman
No abstract text is available yet for this article.
June 2014: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/24225019/parp-inhibitors-for-brca1-2-mutation-associated-and-brca-like-malignancies
#12
REVIEW
J-M Lee, J A Ledermann, E C Kohn
Poly(ADP-ribose)polymerase inhibitors (PARPis) have shown promising activity in patients with BRCA1/2 mutation-associated (BRCA1/2(MUT+)) ovarian and breast cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of sporadic high-grade serous ovarian cancer, and cancers defective in DNA repair pathways, such as prostate, endometrial, and pancreatic cancers. Several PARPis are currently in phase 1/2 clinical investigation, with registration trials now being designed. Olaparib, one of the most studied PARPis, has demonstrated activity in BRCA1/2(MUT+) and BRCA-like sporadic ovarian and breast cancers, and looks promising in prostate and pancreatic cancers...
January 2014: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/23922302/efficacy-of-chemotherapy-in-brca1-2-mutation-carrier-ovarian-cancer-in-the-setting-of-parp-inhibitor-resistance-a-multi-institutional-study
#13
MULTICENTER STUDY
Joo Ern Ang, Charlie Gourley, C Bethan Powell, Hilda High, Ronnie Shapira-Frommer, Vincent Castonguay, Jacques De Greve, Tina Atkinson, Timothy A Yap, Shahneen Sandhu, Susana Banerjee, Lee-May Chen, Michael L Friedlander, Bella Kaufman, Amit M Oza, Ursula Matulonis, Louise J Barber, Iwanka Kozarewa, Kerry Fenwick, Ioannis Assiotis, James Campbell, Lina Chen, Johann S de Bono, Martin E Gore, Christopher J Lord, Alan Ashworth, Stan B Kaye
PURPOSE: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated. EXPERIMENTAL DESIGN: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more...
October 1, 2013: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/23846919/brca-and-pancreatic-cancer
#14
REVIEW
Gregory T Brennan, Valerie Relias, Muhammad Wasif Saif
Germline mutations in BRCA genes have been associated with pancreatic cancer. Laboratory and clinical data suggest that patients with BRCA mutations may be more responsive to therapy consisting of conventional chemotherapy with a poly(ADP-ribose) polymerase inhibitor (PARPi). The most recent data from the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting will be reviewed (Abstracts #11024 and #TPS4144).
July 2013: JOP: Journal of the Pancreas
https://www.readbyqxmd.com/read/23246380/53bp1-expression-in-sporadic-and-inherited-ovarian-carcinoma-relationship-to-genetic-status-and-clinical-outcomes
#15
Kathryn P Pennington, Anneka Wickramanayake, Barbara M Norquist, Christopher C Pennil, Rochelle L Garcia, Kathy J Agnew, Toshiyasu Taniguchi, Piri Welcsh, Elizabeth M Swisher
OBJECTIVES: 53BP1, a critical mediator of the DNA damage response, functions by regulating the balance between homologous recombination (HR) and the more error-prone non-homologous endjoining (NHEJ). Deletion of 53BP1 in brca1 (but not brca2) null cells partially restores HR and reverses sensitivity to poly-ADP-ribose polymerase inhibitors (PARPi). We characterized 53BP1 and BRCA1 expression and their association with clinical outcomes in sporadic and inherited ovarian carcinomas. METHODS: We evaluated 53BP1 and BRCA1 protein expression using immunohistochemistry in 248 ovarian carcinomas and mRNA expression in 89 cases with quantitative reverse transcriptase PCR...
March 2013: Gynecologic Oncology
https://www.readbyqxmd.com/read/23165508/secondary-mutations-in-brca2-associated-with-clinical-resistance-to-a-parp-inhibitor
#16
Louise J Barber, Shahneen Sandhu, Lina Chen, James Campbell, Iwanka Kozarewa, Kerry Fenwick, Ioannis Assiotis, Daniel Nava Rodrigues, Jorge S Reis Filho, Victor Moreno, Joaquin Mateo, L Rhoda Molife, Johann De Bono, Stan Kaye, Christopher J Lord, Alan Ashworth
PARP inhibitors (PARPi) for the treatment of BRCA1 or BRCA2 deficient tumours are currently the focus of seminal clinical trials exploiting the concept of synthetic lethality. Although clinical resistance to PARPi has been described, the mechanism underlying this has not been elucidated. Here, we investigate tumour material from patients who had developed resistance to the PARPi olaparib, subsequent to showing an initial clinical response. Massively parallel DNA sequencing of treatment-naive and post-olaparib treatment biopsies identified tumour-specific BRCA2 secondary mutations in olaparib-resistant metastases...
February 2013: Journal of Pathology
https://www.readbyqxmd.com/read/22983061/evaluation-of-candidate-biomarkers-to-predict-cancer-cell-sensitivity-or-resistance-to-parp-1-inhibitor-treatment
#17
Lenka Oplustilova, Kamila Wolanin, Martin Mistrik, Gabriela Korinkova, Dana Simkova, Jan Bouchal, Rene Lenobel, Jirina Bartkova, Alan Lau, Mark J O'Connor, Jiri Lukas, Jiri Bartek
Impaired DNA damage response pathways may create vulnerabilities of cancer cells that can be exploited therapeutically. One such selective vulnerability is the sensitivity of BRCA1- or BRCA2-defective tumors (hence defective in DNA repair by homologous recombination, HR) to inhibitors of the poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme critical for repair pathways alternative to HR. While promising, treatment with PARP-1 inhibitors (PARP-1i) faces some hurdles, including (1) acquired resistance, (2) search for other sensitizing, non-BRCA1/2 cancer defects and (3) lack of biomarkers to predict response to PARP-1i...
October 15, 2012: Cell Cycle
https://www.readbyqxmd.com/read/22778154/enhancement-of-synthetic-lethality-via-combinations-of-abt-888-a-parp-inhibitor-and-carboplatin-in-vitro-and-in-vivo-using-brca1-and-brca2-isogenic-models
#18
Caroline C Clark, Jeffrey N Weitzel, Timothy R O'Connor
Individuals with an inherited BRCA1 or BRCA2 mutation have an elevated risk of developing breast cancer. The resulting tumors typically lack homologous recombination repair as do a subset of sporadic tumors with acquired BRCA deficiency. Clinical responses to monotherapy with platinum drugs or poly PARP inhibitors (PARPi) have been shown for BRCA-associated cancers. However, there are limited data on combination therapy with PARPi and platinum drugs, the mechanism of action of this combination, and the role of BRCA1 or BRCA2 in chemosensitivity...
September 2012: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/22392482/synthetic-lethality-of-parp-inhibition-in-brca-network-disrupted-tumor-cells-is-associated-with-interferon-pathway-activation-and-enhanced-by-interferon-%C3%AE
#19
Paul Warrener, Sammy Kim, Sybil M G Williams, Matthew Biery, Marcia Gordon, Carlo Toniatti, Michele A Cleary, Peter S Linsley, Michael Carleton
Tumor suppressor genes BRCA1 and BRCA2 function in a complex gene network that regulates homologous recombination and DNA double-strand break repair. Disruption of the BRCA-network through gene mutation, deletion, or RNAi-mediated silencing can sensitize cells to small molecule inhibitors of poly (ADP-ribose) polymerase (PARPi). Here, we demonstrate that BRCA-network disruption in the presence of PARPi leads to the selective induction and enhancement of interferon pathway and apoptotic gene expression in cultured tumor cells...
July 2012: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/21778320/the-mutational-profile-of-sporadic-epithelial-ovarian-carcinoma
#20
REVIEW
S Kalamanathan, V Bates, R Lord, J A Green
Mutations occurring in sporadic epithelial ovarian carcinomas are reviewed and their functional significance in terms of prognosis and prediction of anticancer drug activity are discussed. Alterations in the BRCA1/2 genes, TP53, PTEN, PI3Kinase, KRAS/BRAF and CTNNB1 are described. TP53 is likely to be a driver in high grade serous tumours, but is less useful than BRCA status in prediction of response to the platinum or PARPi agents. It is expected that mutation profiling will become integrated into current morphological/immunohistochemical primary diagnostic assessment of tumours once the cost and quality control issues of the technology are addressed...
August 2011: Anticancer Research
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