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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...
May 1, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29660759/parp-inhibitors-in-breast-cancer-bringing-synthetic-lethality-to-the-bedside
#2
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/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/29615458/an-effective-epigenetic-parp-inhibitor-combination-therapy-for-breast-and-ovarian-cancers-independent-of-brca-mutations
#4
Nicholas Pulliam, Fang Fang, Ali R Ozes, Jessica Tang, Adeoluwa Adewuyi, Harold N Keer, John F Lyons, Stephen B Baylin, Daniela Matei, Harikrishna Nakshatri, Feyruz V Rassool, Kathy D Miller, Kenneth P Nephew
PURPOSE: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair (DDR) and our previous studies demonstrating DNMTis ability to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status...
April 3, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29512470/parp-inhibitors-in-ovarian-cancer
#5
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/29483558/radiosensitization-effect-of-talazoparib-a-parp-inhibitor-on-glioblastoma-stem-cells-exposed-to-low-and-high-linear-energy-transfer-radiation
#6
Paul Lesueur, François Chevalier, Elias A El-Habr, Marie-Pierre Junier, Hervé Chneiweiss, Laurent Castera, Etienne Müller, Dinu Stefan, Yannick Saintigny
Despite continuous improvements in treatment of glioblastoma, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be the presence of glioblastoma cancer stem cells (GSCs), which feature high DNA repair capability. PARP protein plays an important cellular role by detecting the presence of damaged DNA and then activating signaling pathways that promote appropriate cellular responses. Thus, PARP inhibitors (PARPi) have recently emerged as potential radiosensitizing agents...
February 26, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29449416/correction-differential-toxicity-in-patients-with-and-without-dna-repair-mutations-phase-i-study-of-carboplatin-and-talazoparib-in-advanced-solid-tumors
#7
(no author information available yet)
No abstract text is available yet for this article.
February 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29339439/-idh1-2-mutations-sensitize-acute-myeloid-leukemia-to-parp-inhibition-and-this-is-reversed-by-idh1-2-mutant-inhibitors
#8
Remco J Molenaar, Tomas Radivoyevitch, Yasunobu Nagata, Mohammed Khurshed, Bartolomiej Przychodzen, Hideki Makishima, Mingjiang Xu, Fonnet E Bleeker, Johanna W Wilmink, Hetty E Carraway, Sudipto Mukherjee, Mikkael A Sekeres, Cornelis J F van Noorden, Jaroslaw P Maciejewski
Purpose: Somatic mutations in IDH1/2 occur in approximately 20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2MUT enzymes produce D -2-hydroxyglutarate ( D 2HG), which associates with increased DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2 MUT AML is not known. Experimental Design: Well-characterized primary IDH1 MUT , IDH2 MUT , and IDH1/2 WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation, and PARP inhibitors...
April 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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
#9
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/29242215/talazoparib-bests-chemo-for-breast-cancer
#10
(no author information available yet)
Patients with advanced or metastatic HER2-negative breast cancer and germline BRCA1/2 mutations may benefit from talazoparib, according to data from a phase III trial. Compared with chemotherapy, the investigational PARP inhibitor induced some complete responses, prolonged progression-free survival, and improved patients' overall quality of life.
February 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29238749/a-feasibility-study-of-neoadjuvant-talazoparib-for-operable-breast-cancer-patients-with-a-germline-brca-mutation-demonstrates-marked-activity
#11
J K Litton, M Scoggins, D L Ramirez, R K Murthy, G J Whitman, K R Hess, B E Adrada, S L Moulder, C H Barcenas, V Valero, J Schwartz Gomez, E A Mittendorf, A Thompson, T Helgason, G B Mills, H Piwnica-Worms, B K Arun
This study was undertaken to determine the feasibility of enrolling breast cancer patients on a single-agent-targeted therapy trial before neoadjuvant chemotherapy. Specifically, we evaluated talazoparib in patients harboring a deleterious BRCA mutation (BRCA+). Patients with a germline BRCA mutation and ≥1 cm, HER2-negative primary tumors were eligible. Study participants underwent a pretreatment biopsy, 2 months of talazoparib, off-study core biopsy, anthracycline, and taxane-based chemotherapy ± carboplatin, followed by surgery...
2017: NPJ Breast Cancer
https://www.readbyqxmd.com/read/29189915/targeting-brca1-2-deficient-ovarian-cancer-with-cndac-based-drug-combinations
#12
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/29158830/sustained-release-talazoparib-implants-for-localized-treatment-of-brca1-deficient-breast-cancer
#13
Jodi E Belz, Rajiv Kumar, Paige Baldwin, Noelle Castilla Ojo, Ana S Leal, Darlene B Royce, Di Zhang, Anne L van de Ven, Karen T Liby, Srinivas Sridhar
Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1 -deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0...
2017: Theranostics
https://www.readbyqxmd.com/read/29093017/a-population-of-heterogeneous-breast-cancer-patient-derived-xenografts-demonstrate-broad-activity-of-parp-inhibitor-in-brca1-2-wild-type-tumors
#14
Kurt W Evans, Erkan Yuca, Argun Akcakanat, Stephen M Scott, Natalia Paez Arango, Xiaofeng Zheng, Ken Chen, Coya Tapia, Emily Tarco, Agda K Eterovic, Dalliah M Black, Jennifer K Litton, Timothy A Yap, Debu Tripathy, Gordon B Mills, Funda Meric-Bernstam
Background: Breast cancer patients who do not respond to neoadjuvant therapy have a poor prognosis. There is a pressing need for novel targets and models for preclinical testing. Here we report characterization of breast cancer patient-derived xenografts (PDX) largely generated from residual tumors following neoadjuvant chemotherapy. Experimental Design: PDXs were derived from surgical samples of primary or locally recurrent tumors. Normal and tumor DNA sequencing, RNASeq, and reverse phase protein arrays (RPPA) were performed...
November 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28958991/pathway-enriched-gene-signature-associated-with-53bp1-response-to-parp-inhibition-in-triple-negative-breast-cancer
#15
Saima Hassan, Amanda Esch, Tiera Liby, Joe W Gray, Laura M Heiser
Effective treatment of patients with triple-negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients who will most benefit from anti-PARP therapy. We determined the responses of three PARP inhibitors (veliparib, olaparib, and talazoparib) in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved PARP)...
December 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28947502/restricted-delivery-of-talazoparib-across-the-blood-brain-barrier-limits-the-sensitizing-effects-of-parp-inhibition-on-temozolomide-therapy-in-glioblastoma
#16
Sani H Kizilbash, Shiv K Gupta, Kenneth Chang, Ryo Kawashima, Karen E Parrish, Brett L Carlson, Katrina K Bakken, Ann C Mladek, Mark A Schroeder, Paul A Decker, Gaspar J Kitange, Yuqiao Shen, Ying Feng, Andrew A Protter, William F Elmquist, Jann N Sarkaria
Poly ADP-ribose polymerase (PARP) inhibitors, including talazoparib, potentiate temozolomide efficacy in multiple tumor types; however, talazoparib-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates talazoparib ± temozolomide in clinically relevant GBM models. Talazoparib at 1-3 nmol/L sensitized T98G, U251, and GBM12 cells to temozolomide, and enhanced DNA damage signaling and G2 -M arrest in vitro In vivo cyclical therapy with talazoparib (0.15 mg/kg twice daily) combined with low-dose temozolomide (5 mg/kg daily) was well tolerated...
December 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28893315/heterogeneous-drug-penetrance-of-veliparib-and-carboplatin-measured-in-triple-negative-breast-tumors
#17
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/28790114/differential-toxicity-in-patients-with-and-without-dna-repair-mutations-phase-i-study-of-carboplatin-and-talazoparib-in-advanced-solid-tumors
#18
Mallika S Dhawan, Imke H Bartelink, Rahul Raj Aggarwal, Jim Leng, Jenna Z Zhang, Nela Pawlowska, Manuela Terranova-Barberio, Jennifer A Grabowsky, Andrew Gewitz, Amy J Chien, Mark Moasser, Robin K Kelley, Tayeba Maktabi, Scott Thomas, Pamela N Munster
Purpose: The PARP inhibitor (PARPi) talazoparib may potentiate activity of chemotherapy and toxicity in cells vulnerable to DNA damage. Experimental Design: This phase I study evaluated the safety, tolerability, pharmacokinetics, and efficacy of talazoparib and carboplatin. Pharmacokinetic modeling explored associations between DNA vulnerability and hematologic toxicity. Results: Twenty-four patients (eight males; 16 females) with solid tumors were enrolled in four cohorts at 0.75 and 1 mg daily talazoparib and weekly carboplatin (AUC 1 and 1...
November 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28766886/small-cell-lung-carcinoma-cell-line-screen-of-etoposide-carboplatin-plus-a-third-agent
#19
Beverly A Teicher, Thomas Silvers, Michael Selby, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Ralph Parchment, Julia Krushkal, Dmitriy Sonkin, Larry Rubinstein, Joel Morris, David Evans
The SCLC combination screen examined a 9-point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in all SCLC lines...
August 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28677821/development-and-validation-of-a-high-performance-liquid-chromatography-method-for-the-quantification-of-talazoparib-in-rat-plasma-application-to-plasma-protein-binding-studies
#20
Mahendra Kumar Hidau, Srikanth Kolluru, Srinath Palakurthi
A sensitive and selective RP-HPLC method has been developed and validated for the quantification of a highly potent poly ADP ribose polymerase inhibitor talazoparib (TZP) in rat plasma. Chromatographic separation was performed with isocratic elution method. Absorbance for TZP was measured with a UV detector (SPD-20A UV-vis) at a λmax of 227 nm. Protein precipitation was used to extract the drug from plasma samples using methanol-acetonitrile (65:35) as the precipitating solvent. The method proved to be sensitive and reproducible over a 100-2000 ng/mL linearity range with a lower limit of quantification (LLQC) of 100 ng/mL...
February 2018: Biomedical Chromatography: BMC
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