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Parp inhibitor ovarian ca

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https://www.readbyqxmd.com/read/29774075/plectin-targeted-liposomes-enhance-the-therapeutic-efficacy-of-a-parp-inhibitor-in-the-treatment-of-ovarian-cancer
#1
Siva Sai Krishna Dasa, Galina Diakova, Ryo Suzuki, Anne M Mills, Michael F Gutknecht, Alexander L Klibanov, Jill K Slack-Davis, Kimberly A Kelly
Advances in genomics and proteomics drive precision medicine by providing actionable genetic alterations and molecularly targeted therapies, respectively. While genomic analysis and medicinal chemistry have advanced patient stratification with treatments tailored to the genetic profile of a patient's tumor, proteomic targeting has the potential to enhance the therapeutic index of drugs like poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors in breast and ovarian cancer patients with BRCA1/2 mutations have shown promise...
2018: Theranostics
https://www.readbyqxmd.com/read/29767896/-high-grade-serous-ovarian-cancer-2018-advances-and-controversies
#2
Nuria Mederos, Anita Wolfer, Patrice Mathevet, Maged Zaher, Apostolos Sarivalasis
The primary treatment of ovarian cancer consists in a complete surgical debulking followed by adjuvant chemotherapy combining platinum with taxanes. Despite this treatment, patient survival has remained stable over the last 20 years. Recently, advances in the sequence, regimens, and route of administration of treatment have enhanced effectiveness and reduced toxicity. Targeted anti-angiogenic therapy and recently PARP inhibitors are now complementing standard treatment and have improved patient progression-free survival...
May 16, 2018: Revue Médicale Suisse
https://www.readbyqxmd.com/read/29767688/safety-and-dose-modification-for-patients-receiving-niraparib
#3
J S Berek, U A Matulonis, U Peen, P Ghatage, S Mahner, A Redondo, A Lesoin, N Colombo, I Vergote, O Rosengarten, J Ledermann, M Pineda, S Ellard, J Sehouli, A Gonzalez-Martin, D Berton-Rigaud, R Madry, A Reinthaller, S Hazard, W Guo, M R Mirza
Background: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved in the United States and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to TEAE was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was performed to identify clinical parameters that predict dose reductions...
May 14, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29767248/combined-treatment-with-pi3k-inhibitor-bkm120-and-parp-inhibitor-olaparib-is-effective-in-inhibiting-the-gastric-cancer-cells-with-arid1a-deficiency
#4
Lin Yang, Guanghai Yang, Yingjun Ding, Yu Huang, Shunfang Liu, Lei Zhou, Wenjie Wei, Jing Wang, Guangyuan Hu
Dual blockade of phosphoinositide 3-kinase (PI3K) and poly(ADP-ribose) polymerase (PARP) has been revealed to be an effective treatment strategy for breast, ovarian and prostate cancer. However, the efficacy of this combination for the treatment of gastric cancer, and potential predictive therapeutic biomarkers remain unclear. Recent evidence suggests that the deficiency of AT-rich interactive domain containing protein 1A (ARID1A), which is a crucial chromatin remodeling gene, sensitizes tumor cells to PI3K and PARP inhibitors...
May 16, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29750868/brca-status-does-not-predict-synergism-of-a-carboplatin-and-olaparib-combination-in-high-grade-serous-ovarian-cancer-cell-lines
#5
Yen Ting Shen, James C Evans, Gaetano Zafarana, Christine Allen, Micheline Piquette-Miller
Over 50% of epithelial ovarian cancers express the BRCAness profile that leads to a dysfunctional homologous recombination repair system. The combination of a dysfunctional homologous recombination repair system and a poly (ADP-ribose) polymerase (PARP) inhibitor results in a synthetic lethal phenotype. The PARP inhibitor olaparib, approved as a monotherapy for patients with a germline BRCA mutation, has shown promising results in preclinical studies when combined with DNA damaging agents such as carboplatin...
May 11, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29750420/latest-clinical-evidence-and-further-development-of-parp-inhibitors-in-ovarian-cancer
#6
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/29735311/inadequate-rates-of-brca-testing-with-its-negative-consequences-for-women-with-epithelial-ovarian-cancer-and-their-families-an-overview-of-the-literature
#7
P J Hoskins
Fifteen per cent of women with epithelial ovarian cancer possess inherited mutations in the BRCA genes. Knowledge of her BRCA status is important to her and her family. Poly(ADP-ribose) polymerase (PARP) inhibitors provide a new therapeutic option for her. For her family it provides the opportunity for the prevention of what otherwise is often a lethal disease. To access these opportunities, the mandatory first step is testing the woman with the cancer. However, referral rates for genetic counselling and subsequent BRCA testing are low, in the of 10-30% range...
May 5, 2018: Clinical Oncology: a Journal of the Royal College of Radiologists
https://www.readbyqxmd.com/read/29717031/piperine-functions-as-a-tumor-suppressor-for-human-ovarian-tumor-growth-via-activation-of-jnk-p38-mapk-mediated-intrinsic-apoptotic-pathway
#8
Lihui Si, Ruiqi Yang, Ruixin Lin, Shuli Yang
Piperine, a kind of natural alkaloid found in the fruit of black (Piper nigrum Linn) and long (Piper longum Linn), has shown antitumor activities toward various cancer cell lines. However, the antitumor effects of piperine on ovarian cancer and the underlying mechanism are not fully elucidated. Our result showed that piperine reduced the cell viability of A2780 cells in a concentration and time-dependent manner, but has not any effect on normal ovarian cells. Flow cytometric analysis revealed that piperine suppressed cells proliferation via induction of apoptosis, which was followed by release of mitochondrial cytochrome c to cytosol, activation of caspase-3, and -9, as well as cleaved PARP...
May 1, 2018: Bioscience Reports
https://www.readbyqxmd.com/read/29703482/anti-angiogenesis-for-cancer-current-status-and-prospects
#9
Massimo Russo, Raffaella Giavazzi
Since the establishment of tumor angiogenesis as a therapeutic target, new, effective antiangiogenic agents have been developed. Despite their demonstrable clinical benefits, these therapies often have only a short-term effect, with limited impact on the overall survival of cancer patients. A question in the development of these drugs concerns their optimal use in combination regimens with newer therapeutic strategies. Here we review the current therapeutic settings combining anti-angiogenesis inhibitors with chemotherapy, PARP inhibitors or immune checkpoint blockers, focusing on ovarian cancer as tumor model...
April 2018: Thrombosis Research
https://www.readbyqxmd.com/read/29685880/integrative-kinome-profiling-identifies-mtorc1-2-inhibition-as-treatment-strategy-in-ovarian-clear-cell-carcinoma
#10
Joseph J Caumanns, Katrien Berns, G Bea A Wisman, Rudolf S N Fehrmann, Tushar Tomar, Harry Klip, Gert Jan Meersma, E Marielle Hijmans, Annemiek Gennissen, Evelien W Duiker, Desiree Weening, Hiroaki Itamochi, Roelof Jc Kluin, An K L Reyners, Michael J Birrer, Helga B Salvesen, Ignace Vergote, Els Van Nieuwenhuysen, James D Brenton, Elena I Braicu, Jolanta Kupryjanczyk, Beata Spiewankiewicz, Lorenza Mittempergher, Rene Bernards, Ate G J van der Zee, Steven de Jong
PURPOSE: Advanced stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in OCCC patients and test druggability of downstream affected pathways in OCCC models. EXPERIMENTAL DESIGN: In a large set of OCCC patients (n=124), the human kinome (518 kinases) and additional cancer related genes were sequenced and copy number alterations were determined...
April 23, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29684820/increased-oxidative-stress-mediates-the-antitumor-effect-of-parp-inhibition-in-ovarian-cancer
#11
Dong Hou, Zhaojian Liu, Xiuhua Xu, Qiao Liu, Xiyu Zhang, Beihua Kong, Jian-Jun Wei, Yaoqin Gong, Changshun Shao
PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells...
March 30, 2018: Redox Biology
https://www.readbyqxmd.com/read/29672168/rucaparib-a-new-treatment-option-for-ovarian-cancer
#12
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/29669295/a-quantitative-chemotherapy-genetic-interaction-map-reveals-factors-associated-with-parp-inhibitor-resistance
#13
Hsien-Ming Hu, Xin Zhao, Swati Kaushik, Lilliane Robillard, Antoine Barthelet, Kevin K Lin, Khyati N Shah, Andy D Simmons, Mitch Raponi, Thomas C Harding, Sourav Bandyopadhyay
Chemotherapy is used to treat most cancer patients, yet our understanding of factors that dictate response and resistance to such drugs remains limited. We report the generation of a quantitative chemical-genetic interaction map in human mammary epithelial cells charting the impact of the knockdown of 625 genes related to cancer and DNA repair on sensitivity to 29 drugs, covering all classes of chemotherapy. This quantitative map is predictive of interactions maintained in other cell lines, identifies DNA-repair factors, predicts cancer cell line responses to therapy, and prioritizes synergistic drug combinations...
April 17, 2018: Cell Reports
https://www.readbyqxmd.com/read/29664016/the-evolving-landscape-of-predictive-biomarkers-of-response-to-parp-inhibitors
#14
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/29660759/parp-inhibitors-in-breast-cancer-bringing-synthetic-lethality-to-the-bedside
#15
REVIEW
Anita A Turk, Kari B Wisinski
Individuals with breast and ovarian cancer susceptibility gene 1 (BRCA1) or BRCA2 germline mutations have a significantly increased lifetime risk for breast and ovarian cancers. BRCA-mutant cancer cells have abnormal homologous recombination (HR) repair of DNA. In these tumors, the base excision repair (BER) pathway is important for cell survival. The poly(adenosine diphosphate-ribose) polymerase (PARP) enzymes play a key role in BER, and PARP inhibitors are effective in causing cell death in BRCA-mutant cells while sparing normal cells-a concept called synthetic lethality...
April 16, 2018: Cancer
https://www.readbyqxmd.com/read/29650809/-molecular-targeted-therapies-for-hereditary-cancer-syndrome
#16
Hideki Shimodaira
Development of molecular targeted drugs has achieved remarkable improvement of systemic cancer therapy. Recently, the several molecular targeted drugs have become available which associated with the status of responsible genes for hereditary cancer syndrome. These drugs would allow to establish specific strategy for hereditary cancer syndrome or sporadic cancers with similar biological phenotype with hereditary cancer. Genetic tests for the diagnosis of hereditary cancer syndrome will have the meaning of biomarker for predicting the efficacy of these molecular targeted drugs...
April 2018: Gan to Kagaku Ryoho. Cancer & Chemotherapy
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
#17
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
#18
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/29627080/assessment-and-management-of-diarrhea-following-vegf-receptor-tki-treatment-in-patients-with-ovarian-cancer
#19
REVIEW
Joyce Liu, Shibani Nicum, Peter Reichardt, Kenneth Croitoru, Beate Illek, Manuela Schmidinger, Catherine Rogers, Christin Whalen, Gordon C Jayson
Angiogenesis is a proven clinical target for the treatment of advanced epithelial ovarian cancer. Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) offer patients potential new treatment regimens as they can be given as monotherapy, in combination with poly(ADP-ribose) polymerase (PARP) inhibitors, or with and following cytotoxic chemotherapy. If VEGFR-TKIs are licensed for use in ovarian cancer, patients will require prompt and effective management of adverse events, including diarrhea, to optimize compliance and benefit...
April 4, 2018: Gynecologic Oncology
https://www.readbyqxmd.com/read/29620474/pharmacokinetic-drug-evaluation-of-niraparib-for-the-treatment-of-ovarian-cancer
#20
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
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