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Anosheh Afghahi, Kirsten M Timms, Shaveta Vinayak, Kristin C Jensen, Allison W Kurian, Robert W Carlson, Pei-Jen Chang, Elizabeth A Schackmann, Anne-Renee Hartman, James M Ford, Melinda L Telli
BACKGROUND: In germline BRCA1 or BRCA2 (BRCA1/2) mutation carriers, restoration of tumor BRCA1/2 function by a secondary mutation is recognized as a mechanism of resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We evaluated this mechanism of resistance in newly diagnosed BRCA1/2-mutant breast cancer patients with poor response to neoadjuvant platinum-based therapy. METHODS: PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin and iniparib in patients with stage I-IIIA triple-negative or BRCA1/2 mutation-associated breast cancer (n=80)...
January 13, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Melinda L Telli, Kirsten M Timms, Julia Reid, Bryan Hennessy, Gordon B Mills, Kristin C Jensen, Zoltan Szallasi, William T Barry, Eric P Winer, Nadine M Tung, Steven J Isakoff, Paula D Ryan, April Greene-Colozzi, Alexander Gutin, Zaina Sangale, Diana Iliev, Chris Neff, Victor Abkevich, Joshua T Jones, Jerry S Lanchbury, Anne-Renee Hartman, Judy E Garber, James M Ford, Daniel P Silver, Andrea L Richardson
PURPOSE: BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). EXPERIMENTAL DESIGN: We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy...
August 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Corey Saba, Melissa Paoloni, Christina Mazcko, William Kisseberth, Jenna H Burton, Annette Smith, Heather Wilson-Robles, Sara Allstadt, David Vail, Carolyn Henry, Susan Lana, E J Ehrhart, Brad Charles, Michael Kent, Jessica Lawrence, Kristine Burgess, Antonella Borgatti, Steve Suter, Paul Woods, Ira Gordon, Patricia Vrignaud, Chand Khanna, Amy K LeBlanc
Development of iniparib as an anti-cancer agent was hindered in part by lingering questions regarding its mechanism of action, the activity of its metabolites, and their potential accumulation in tumors. Due to strong similarities in metabolism of iniparib between humans and dogs, a veterinary clinical trial in pet dogs with spontaneous cancers was designed to answer specific questions pertaining to pharmacokinetic exposures and tolerability of iniparib. Dogs were treated with iniparib alone and in combination with carboplatin chemotherapy...
2016: PloS One
Sonia Ávila-Arroyo, Gema Santamaría Nuñez, Luis Francisco García-Fernández, Carlos M Galmarini
PURPOSE: Trabectedin induces synthetic lethality in tumor cells carrying defects in homologous recombinant DNA repair. We evaluated the effect of concomitant inhibition of nucleotide-excision repair and poly (ADP-ribose) polymerase (PARP) activity with trabectedin and PARP inhibitors, respectively, and whether the synthetic lethality effect had the potential for a synergistic effect in breast cancer cell lines. Additionally, we investigated if this approach remained effective in BRCA1-positive breast tumor cells...
December 2015: Journal of Breast Cancer
Katherine M Bell-McGuinn, Jason A Konner, William P Tew, Martee L Hensley, Alexia Iasonos, Eric Charpentier, Svetlana Mironov, Paul Sabbatini, Carol Aghajanian
OBJECTIVE: The aim of the study was to evaluate the activity and tolerability of iniparib monotherapy in women with BRCA1 or BRCA2-associated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. METHODS AND MATERIALS: Eligible patients had advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer, germline BRCA1 or BRCA2 mutation, measurable disease, and at least 1 previous treatment regimen of platinum/taxane chemotherapy. Patients received iniparib 8 mg/kg intravenously on days 1 and 4 weekly, with imaging every 8 weeks...
February 2016: International Journal of Gynecological Cancer
Shinya Matsuzaki, Kiyoshi Yoshino, Yutaka Ueda, Satoko Matsuzaki, Mamoru Kakuda, Akiko Okazawa, Tomomi Egawa-Takata, Eiji Kobayashi, Tadashi Kimura
Advances in surgical and medical treatments for ovarian cancer have improved prognoses. Platinum drugs in particular are pivotal for the medical treatment of ovarian cancer. However, previous studies have revealed that some histological subtypes, such as clear cell carcinoma, are resistant to medical treatment, including that with platinum drugs. Consequently, the clinical prognosis of advanced clear cell carcinoma is remarkably inferior, primarily because of its chemoresistant behavior. The prevalence of clear cell carcinoma is approximately 5 % in the West, but in Japan, its prevalence is particularly high, at approximately 25 %...
2015: Cancer Cell International
Antonio Llombart-Cussac, Begoña Bermejo, Cristian Villanueva, Suzette Delaloge, Serafín Morales, Judith Balmaña, Kepa Amillano, Hervé Bonnefoi, Ana Casas, Luis Manso, Henri Roché, Santiago Gonzalez-Santiago, Joaquín Gavilá, Pedro Sánchez-Rovira, Serena Di Cosimo, Nadia Harbeck, Eric Charpentier, Ignacio Garcia-Ribas, Nina Radosevic-Robin, Claudia Aura, Jose Baselga
Iniparib is an investigational agent with antitumor activity of controversial mechanism of action. Two previous trials in advanced triple-negative breast cancer (TNBC) in combination with gemcitabine and carboplatin showed some evidence of efficacy that was not confirmed. This phase II randomized neoadjuvant study was designed to explore its activity and tolerability with weekly paclitaxel (PTX) as neoadjuvant treatment in TNBC patients. 141 patients with Stage II-IIIA TNBC were randomly assigned to receive PTX (80 mg/m(2), d1; n = 47) alone or in combination with iniparib, either once-weekly (PWI) (11...
November 2015: Breast Cancer Research and Treatment
Jaishri O Blakeley, Stuart A Grossman, Tom Mikkelsen, Myrna R Rosenfeld, David Peereboom, L Burt Nabors, Andrew S Chi, Gary Emmons, Ignacio Garcia Ribas, Jeffrey G Supko, Serena Desideri, Xiaobu Ye
Iniparib is a prodrug that converts to highly reactive cytotoxic metabolites intracellularly with activity in preclinical glioma models. We investigated the maximum tolerated dose (MTD) of iniparib with monthly (m) and continuous (c) temozolomide (TMZ) dosing schedules in patients with malignant gliomas (MG). Adults with newly diagnosed MG who had successfully completed ≥80% of radiation (RT) and TMZ without toxicity received mTMZ dosing (150-200 mg/m(2) days 1-5/28 days) or cTMZ dosing (75 mg/m(2)/days × 6 weeks) in conjunction with iniparib (i...
October 2015: Journal of Neuro-oncology
Józefa Węsierska-Gądek, Matthias Mauritz, Goran Mitulovic, Maria Cupo
BRCA1/2-mutant cells are hypersensitive to inactivation of poly(ADP-ribose) polymerase 1 (PARP-1). We recently showed that inhibition of PARP-1 by NU1025 is strongly cytotoxic for BRCA1-positive BT-20 cells, but not BRCA1-deficient SKBr-3 cells. These results raised the possibility that other PARP-1 inhibitors, particularly those tested in clinical trials, may be more efficacious against BRCA1-deficient SKBr-3 breast cancer cells than NU1025. Thus, in the presented study the cytotoxicity of four PARP inhibitors under clinical evaluation (olaparib, rucaparib, iniparib and AZD2461) was examined and compared to that of NU1025...
December 2015: Journal of Cellular Biochemistry
Banu Arun, Ugur Akar, Angelica M Gutierrez-Barrera, Gabriel N Hortobagyi, Bulent Ozpolat
PARP inhibitors are considered promising anticancer agents and currently being tested in clinical trials in hereditary breast cancer patients harboring mutations in BRCA1 and BRCA2 genes. In this study, we investigated the antiproliferative effects and mechanism of PARP inhibitors ABT-888 (Veliparib), BSI-201 (Iniparib) and AZD228 (Olaparib) in breast cancer cell lines with BRCA1 or BRCA2 mutations and 9 different BRCA wild-type cell lines with BRCA1 allelic loss. We found that AZD2281 was the most potent in the PARP inhibitors and induces significant growth inhibition (~95%) in BRCA1 mutant (HCC‑1937, MDA-MB-436, and SUM-149PT) and BRCA2 mutant (HCC‑1428) cell lines...
July 2015: International Journal of Oncology
Melinda L Telli, Kristin C Jensen, Shaveta Vinayak, Allison W Kurian, Jafi A Lipson, Patrick J Flaherty, Kirsten Timms, Victor Abkevich, Elizabeth A Schackmann, Irene L Wapnir, Robert W Carlson, Pei-Jen Chang, Joseph A Sparano, Bobbie Head, Lori J Goldstein, Barbara Haley, Shaker R Dakhil, Julia E Reid, Anne-Renee Hartman, Judith Manola, James M Ford
PURPOSE: This study was designed to assess efficacy, safety, and predictors of response to iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. PATIENTS AND METHODS: This single-arm phase II study enrolled patients with stage I to IIIA (T ≥ 1 cm) estrogen receptor-negative (≤ 5%), progesterone receptor-negative (≤ 5%), and human epidermal growth factor receptor 2-negative or BRCA1/2 mutation-associated breast cancer...
June 10, 2015: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Joyce O'Shaughnessy, Lee Schwartzberg, Michael A Danso, Kathy D Miller, Hope S Rugo, Marcus Neubauer, Nicholas Robert, Beth Hellerstedt, Mansoor Saleh, Paul Richards, Jennifer M Specht, Denise A Yardley, Robert W Carlson, Richard S Finn, Eric Charpentier, Ignacio Garcia-Ribas, Eric P Winer
PURPOSE: There is a lack of treatments providing survival benefit for patients with metastatic triple-negative breast cancer (mTNBC), with no standard of care. A randomized phase II trial showed significant benefit for gemcitabine, carboplatin, and iniparib (GCI) over gemcitabine and carboplatin (GC) in clinical benefit rate, response rate, progression-free survival (PFS), and overall survival (OS). Here, we formally compare the efficacy of these regimens in a phase III trial. PATIENTS AND METHODS: Patients with stage IV/locally recurrent TNBC who had received no more than two previous chemotherapy regimens for mTNBC were randomly allocated to gemcitabine 1,000 mg/m(2) and carboplatin area under the curve 2 (days 1 and 8) alone or GC plus iniparib 5...
December 1, 2014: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
S Novello, B Besse, E Felip, F Barlesi, J Mazieres, G Zalcman, J von Pawel, M Reck, F Cappuzzo, D Ferry, E Carcereny, A Santoro, I Garcia-Ribas, G Scagliotti, J-C Soria
BACKGROUND: Iniparib is a novel anticancer agent initially considered a poly (ADP-ribose) polymerase (PARP) inhibitor, but subsequently shown to act via non-selective protein modification through cysteine adducts. This randomized phase II study investigated the addition of iniparib to gemcitabine-cisplatin in metastatic non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Patients with histologically confirmed stage IV NSCLC were randomized 2 : 1 to receive gemcitabine (1250 mg/m(2), days 1/8) and cisplatin (75 mg/m(2), day 1) with [gemcitabine/cisplatin/iniparib (GCI)] or without [gemcitabine/cisplatin (GC)] iniparib (5...
November 2014: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Carey Anders, Allison M Deal, Vandana Abramson, Minetta C Liu, Anna M Storniolo, John T Carpenter, Shannon Puhalla, Rita Nanda, Amal Melhem-Bertrandt, Nancy U Lin, P Kelly Marcom, Catherine Van Poznak, Vered Stearns, Michelle Melisko, J Keith Smith, Olga Karginova, Joel Parker, Jonathan Berg, Eric P Winer, Amy Peterman, Aleix Prat, Charles M Perou, Antonio C Wolff, Lisa A Carey
Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks...
August 2014: Breast Cancer Research and Treatment
Christian Jekimovs, Emma Bolderson, Amila Suraweera, Mark Adams, Kenneth J O'Byrne, Derek J Richard
The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult to a cell's genetic material and can lead to genomic instability, apoptosis, or senescence. Incorrectly repaired DNA DSBs have the potential to produce chromosomal translocations and genomic instability, potentially leading to cancer. The prevalence of DNA DSBs in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers...
2014: Frontiers in Oncology
Annalisa Bramati, Serena Girelli, Valter Torri, Gabriella Farina, Elena Galfrascoli, Sheila Piva, Anna Moretti, Maria Chiara Dazzani, Paola Sburlati, Nicla Maria La Verde
Metastatic triple-negative breast cancer (mTNBC) represents 15% of invasive breast cancers. Prognosis is poor, and there is no specific target therapy but biological agents combined with chemotherapy may be effective. To assess the role of biological agents in metastatic triple-negative breast cancer we performed a systematic review of phase III randomized controlled trials published from January 2006 to February 2013 and presentations at ESMO, ASCO, and SABCS congresses in 2010-2012. We consulted PubMed and ClinicalTrials...
June 2014: Cancer Treatment Reviews
Otávio Clark, Tobias Engel Ayer Botrel, Luciano Paladini, Mariana Bhering Andrade Ferreira
OBJECTIVE: To perform a systematic review and meta-analysis of randomized controlled trials that compared the efficacy of targeted therapy to conventional chemotherapy (CT) in patients with metastatic triple-negative breast cancer (TNBC). METHODS: Several databases were searched, including Medline, Embase, LILACS, and CENTRAL. The primary end point was progression-free survival (PFS). We performed a meta-analysis of the published data. The results are expressed as hazard ratio (HR) or risk ratio, with their corresponding 95% confidence intervals (95% CIs)...
2014: Core Evidence
Gunjan Sinha
No abstract text is available yet for this article.
January 2014: Journal of the National Cancer Institute
Maria Saveria Gilardini Montani, Andrea Prodosmo, Venturina Stagni, Dania Merli, Laura Monteonofrio, Veronica Gatti, Maria Pia Gentileschi, Daniela Barilà, Silvia Soddu
BACKGROUND: Mutations in the DNA damage response (DDR) factors, breast cancer 1 (BRCA1) and BRCA2, sensitize tumor cells to poly(ADP-ribose) polymerase (PARP) inhibitors. The ataxia telangiectasia mutated (ATM) kinase is a key DDR protein whose heterozygous germline mutation is a moderate-risk factor for developing breast cancer. In this study, we examined whether ATM inactivation in breast cancer cell lines confers sensitivity to PARP inhibitors. METHODS: Wild-type BRCA1/2 breast cancer cells (i...
2013: Journal of Experimental & Clinical Cancer Research: CR
Joaquin Mateo, Michael Ong, David S P Tan, Michael A Gonzalez, Johann S de Bono
Several drugs targeting poly(ADP-ribose) polymerase (PARP) enzymes are under development. Responses have been observed in patients with germline mutations in BRCA1 and BRCA2, with further data supporting antitumour activity of PARP inhibitors in sporadic ovarian cancer. Strategies to identify other predictive biomarkers remain under investigation. Iniparib was purported to be a PARP inhibitor that showed promising results in randomized phase II trials in patients with triple-negative breast cancer. Negative results from a phase III study in this disease setting, however, tempered enthusiasm for this agent...
December 2013: Nature Reviews. Clinical Oncology
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