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Steven J Isakoff, Shannon Puhalla, Susan M Domchek, Michael Friedlander, Bella Kaufman, Mark Robson, Melinda L Telli, Véronique Diéras, Hyo Sook Han, Judy E Garber, Eric F Johnson, David Maag, Qin Qin, Vincent L Giranda, Stacie P Shepherd
Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I-III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609)...
October 14, 2016: Future Oncology
Jennifer McLachlan, Angela George, Susana Banerjee
ABSTRACTRecent advances in our understanding of the molecular biology of epithelial ovarian cancer have led to the development of a number of targeted therapies, including poly-ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Early studies have shown significant efficacy for PARP inhibitors in patients with germline BRCA1/2 mutations. It has become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this therapeutic approach...
September 24, 2016: Tumori
Wijith Munasinghe, Sven Stodtmann, Anthony Tolcher, Emiliano Calvo, Michael Gordon, Mathilde Jalving, Judith de Vos-Geelen, Diane Medina, Dennis Bergau, Silpa Nuthalapati, David Hoffman, Stacie Shepherd, Hao Xiong
PURPOSE: Veliparib (ABT-888) is an orally bioavailable potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and PARP-2. This phase 1 study evaluated the effect of veliparib on corrected QT interval using Fridericia's formula (QTcF). METHODS: Eligible patients with advanced solid tumors received single-dose oral veliparib (200 mg or 400 mg) or placebo in a 6-sequence, 3-period crossover design. The primary endpoint was the difference in the mean baseline-adjusted QTcF between 400 mg veliparib and placebo (∆∆QTcF) at six post-dose time points...
October 5, 2016: Cancer Chemotherapy and Pharmacology
Jing Lu, Renwei Zhang, Huiqi Hong, Zuolong Yang, Duanping Sun, Shuya Sun, Xiaolei Guo, Jiantao Ye, Zhuoming Li, Peiqing Liu
The Forkhead box-containing protein, O subfamily 3 (FoxO3) transcription factor negatively regulates myocardial hypertrophy, and its transcriptional activity is finely conditioned by diverse posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, methylation and glycosylation. Here, we introduce a novel modification of the FoxO3 protein in cardiomyocytes: poly(ADP-ribosyl)ation (PARylation) mediated by poly(ADP-ribose) polymerase-1 (PARP1). This process catalyzes the NAD(+)-dependent synthesis of polymers of ADP-ribose (PAR) and their subsequent attachment to target proteins by PARPs...
October 4, 2016: Biochimica et Biophysica Acta
Lihua Wang, Priya Balasubramanian, Alice P Chen, Shivaani Kummar, Yvonne A Evrard, Robert J Kinders
Circulating tumor cells (CTCs), which are captured from blood with anti-epithelial cell adhesion molecule (EpCAM) antibodies, have established prognostic value in specific epithelial cancers, but less is known about their utility for assessing patient response to molecularly targeted agents via measurement of pharmacodynamic (PD) endpoints. We discuss the use of CellSearch (Janssen Diagnostics, LLC, Raritan, NJ) CTC isolation technology for monitoring PD response in early phase trials. We present representative data from three clinical trials with the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888) suggesting that CTCs can be used to measure PD effects...
August 2016: Seminars in Oncology
Vinod Vijay Subhash, Shi Hui Tan, Mei Shi Yeo, Fui Leng Yan, Praveen C Peethala, Natalia Liem, Vaidehi Krishnan, Wei-Peng Yong
Identification of synthetically lethal cellular targets and synergistic drug combinations are important in cancer chemotherapy as they help to overcome treatment resistance and increase efficacy. The Ataxia Telangiectasia Mutated (ATM) kinase is a nuclear protein that plays a major role in the initiation of DNA repair signalling and cell cycle check points during DNA damage. Although ATM was shown to be associated with poor prognosis in gastric cancer, its implications as a predictive biomarker for cancer chemotherapy remains unexplored...
September 16, 2016: Molecular Cancer Therapeutics
Y Somnay, S Lubner, H Gill, J B Matsumura, H Chen
Monoagent DNA-alkylating chemotherapies like dacarbazine are among a paucity of medical treatments for advanced carcinoid tumors, but are limited by host toxicity and intrinsic chemoresistance through the base excision repair (BER) pathway via poly (ADP-ribose) polymerase (PARP). Hence, inhibitors of PARP may potentiate DNA-damaging agents by blocking BER and DNA restoration. We show that the PARP inhibitor ABT-888 (Veliparib) enhances the cytotoxic effects of dacarbazine in carcinoids. Two human carcinoid cell lines (BON and H727) treated with a combination of ABT-888 and dacarbazine resulted in synergistic growth inhibition signified by combination indices <1 on the Chou-Talalay scale...
September 16, 2016: Cancer Gene Therapy
Keith W Pratz, Michelle A Rudek, Ivana Gojo, Mark R Litzow, Michael A McDevitt, Jiuping Jay Ji, Larry Karnitz, James G Herman, Robert Kinders, B Douglas Smith, Steven D Gore, Hetty Carraway, Margaret M Showel, Douglas E Gladstone, Mark J Levis, Hua-Ling Tsai, Gary L Rosner, Alice Chen, Scott H Kaufmann, Judith Karp
PURPOSE: The poly(ADP-ribose) polymerase (PARP) inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone. EXPERIMENTAL DESIGN: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPNs) and chronic myelomonocytic leukemia (CMML)...
August 22, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ivana Gojo, Jan H Beumer, Keith W Pratz, Michael A McDevitt, Maria R Baer, Amanda L Blackford, B Douglas Smith, Steven D Gore, Hetty Carraway, Margaret M Showel, Mark J Levis, Amy Dezern, Douglas E Gladstone, Jiuping Jay Ji, Lihua Wang, Robert Kinders, Marie Pouquet, Ismail Ali-Walbi, Michelle A Rudek, Weijie Poh, James G Herman, Larry Karnitz, Scott H Kaufmann, Alice Chen, Judith Karp
PURPOSE: In preclinical studies the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies. EXPERIMENTAL DESIGN: Patients received veliparib (20-200 mg once a day on day 1 and twice daily on days 4-12 in cycle 1 [days 1-8 in cycle {greater than or equal to}2]) and temozolomide (150-200 mg/m(2) daily on days 3-9 in cycle 1 [days 1-5 in cycle {greater than or equal to}2]) every 28-56 days...
August 8, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Charlotte R Lemech, Rachel Williams, Stephen R Thompson, Brian McCaughan, Melvin Chin
BACKGROUND: Follicular dendritic cell sarcoma is a rare tumour with clinical behaviour covering a spectrum from indolent to aggressive disease. Treatment recommendations are currently based on case reports and small series describing combinations of surgery, chemotherapy and radiotherapy providing the best patient outcomes. Recent knowledge on molecular aberrations in this disease have not yet impacted on therapeutic decisions. CASE PRESENTATION: We describe a case of progressive follicular dendritic cell sarcoma of the lung and pleura, treated based on knowledge of the tumour's molecular aberrations...
2016: BMC Research Notes
Yasunori Tome, Fuminari Uehara, Shinji Miwa, Shuya Yano, Sumiyuki Mii, Elena V Efimova, Michael Bouvet, Hiroaki Kimura, Hiroyuki Tsuchiya, Fuminori Kanaya, Robert M Hoffman
BACKGROUND: The ability to image DNA repair in cancer cells after irradiation, as well as its inhibition by potential therapeutic agents, is important for the further development of effective cancer therapy. 53BP1 is a DNA repair protein that is overexpressed and forms foci when double-stranded DNA breaks occur in DNA. MATERIALS AND METHODS: The re-localization of green fluorescent protein (GFP) fused to the chromatin-binding domain of 53BP1 to form foci was imaged after UVC irradiation of breast and pancreatic cancer cells expressing 53BP1-GFP using confocal microscopy...
August 2016: Anticancer Research
Subhendu K Das, Ishita Rehman, Arijit Ghosh, Souvik Sengupta, Papiya Majumdar, Biman Jana, Benu Brata Das
Topoisomerase 1 (Top1) is essential for removing the DNA supercoiling generated during replication and transcription. Anticancer drugs like camptothecin (CPT) and its clinical derivatives exert their cytotoxicity by reversibly trapping Top1 in covalent complexes on the DNA (Top1cc). Poly(ADP-ribose) polymerase (PARP) catalyses the addition of ADP-ribose polymers (PAR) onto itself and Top1. PARP inhibitors enhance the cytotoxicity of CPT in the clinical trials. However, the molecular mechanism by which PARylation regulates Top1 nuclear dynamics is not fully understood...
September 30, 2016: Nucleic Acids Research
Jianguo Xu, Handong Wang, Seok Joon Won, Jayinee Basu, David Kapfhamer, Raymond A Swanson
Brain injury resulting from stroke or trauma can be exacerbated by the release of proinflammatory cytokines, proteases, and reactive oxygen species by activated microglia. The microglial activation resulting from brain injury is mediated in part by alarmins, which are signaling molecules released from damaged cells. The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) has been shown to regulate microglial activation after brain injury, and here we show that signaling effects of the alarmin S100B are regulated by PARP-1...
November 2016: Glia
Benjamin H Lok, Eric E Gardner, Valentina E Schneeberger, Andy Ni, Patrice Desmeules, Natasha Rekhtman, Elisa de Stanchina, Beverly A Teicher, Nadeem Riaz, Simon N Powell, John T Poirier, Charles M Rudin
PURPOSE: PARP inhibitors (PARPi) are a novel class of small molecule therapeutics for small cell lung cancer (SCLC). Identification of predictors of response would advance our understanding, and guide clinical application, of this therapeutic strategy. EXPERIMENTAL DESIGN: Efficacy of PARP inhibitors olaparib, rucaparib, and veliparib, as well as etoposide and cisplatin in SCLC cell lines, and gene expression correlates, were analyzed using public datasets. HRD genomic scar scores were calculated from Affymetrix SNP 6...
July 20, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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
Petra Lakatos, Csaba Hegedűs, Nerea Salazar Ayestarán, Ángeles Juarranz, Katalin E Kövér, Éva Szabó, László Virág
A combination of a photosensitizer with light of matching wavelength is a common treatment modality in various diseases including psoriasis, atopic dermatitis and tumors. DNA damage and production of reactive oxygen intermediates may impact pathological cellular functions and viability. Here we set out to investigate the role of the nuclear DNA nick sensor enzyme poly(ADP-ribose) polymerase 1 in photochemical treatment (PCT)-induced tumor cell killing. We found that silencing PARP-1 or inhibition of its enzymatic activity with Veliparib had no significant effect on the viability of A431 cells exposed to 8-methoxypsoralen (8-MOP) and UVA (2...
August 2016: Mutation Research
Aparajitha Vaidyanathan, Lynne Sawers, Anne-Louise Gannon, Probir Chakravarty, Alison L Scott, Susan E Bray, Michelle J Ferguson, Gillian Smith
BACKGROUND: Clinical response to chemotherapy for ovarian cancer is frequently compromised by the development of drug-resistant disease. The underlying molecular mechanisms and implications for prescription of routinely prescribed chemotherapy drugs are poorly understood. METHODS: We created novel A2780-derived ovarian cancer cell lines resistant to paclitaxel and olaparib following continuous incremental drug selection. MTT assays were used to assess chemosensitivity to paclitaxel and olaparib in drug-sensitive and drug-resistant cells±the ABCB1 inhibitors verapamil and elacridar and cross-resistance to cisplatin, carboplatin, doxorubicin, rucaparib, veliparib and AZD2461...
August 9, 2016: British Journal of Cancer
Hope S Rugo, Olufunmilayo I Olopade, Angela DeMichele, Christina Yau, Laura J van 't Veer, Meredith B Buxton, Michael Hogarth, Nola M Hylton, Melissa Paoloni, Jane Perlmutter, W Fraser Symmans, Douglas Yee, A Jo Chien, Anne M Wallace, Henry G Kaplan, Judy C Boughey, Tufia C Haddad, Kathy S Albain, Minetta C Liu, Claudine Isaacs, Qamar J Khan, Julie E Lang, Rebecca K Viscusi, Lajos Pusztai, Stacy L Moulder, Stephen Y Chui, Kathleen A Kemmer, Anthony D Elias, Kirsten K Edmiston, David M Euhus, Barbara B Haley, Rita Nanda, Donald W Northfelt, Debasish Tripathy, William C Wood, Cheryl Ewing, Richard Schwab, Julia Lyandres, Sarah E Davis, Gillian L Hirst, Ashish Sanil, Donald A Berry, Laura J Esserman
BACKGROUND: The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin...
July 7, 2016: New England Journal of Medicine
J A Ledermann
BACKGROUND: Slow progress in improving the outcome of ovarian cancer with chemotherapy over the last decade has stimulated research into molecularly targeted therapy. Poly(ADP-ribose) polymerase (PARP) inhibitors target DNA repair and are specifically active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated BRCA function have HR deficiency (HRD), which is also present in a significant proportion of non-BRCA-mutated ovarian cancer...
April 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Zachary B Jenner, Anil K Sood, Robert L Coleman
Rucaparib camsylate (CO-338; 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt) is a PARP1, 2 and 3 inhibitor. Phase I studies identified a recommended Phase II dose of 600 mg orally twice daily. ARIEL2 Part 1 established a tumor genomic profiling test for homologous recombination loss of heterozygosity quantification using a next-generation sequencing companion diagnostic (CDx). Rucaparib received US FDA Breakthrough Therapy designation for treatment of platinum-sensitive BRCA-mutated advanced ovarian cancer patients who received greater than two lines of platinum-based therapy...
June 2016: Future Oncology
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