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https://www.readbyqxmd.com/read/28109627/a-final-report-of-a-phase-i-study-of-veliparib-abt-888-in-combination-with-low-dose-fractionated-whole-abdominal-radiation-therapy-ldfwar-in-patients-with-advanced-solid-malignancies-and-peritoneal-carcinomatosis-with-a-dose-escalation-in-ovarian-and-fallopian
#1
Kim A Reiss, Joseph M Herman, Deborah Armstrong, Marianna Zahurak, Anthony Fyles, Anthony Brade, Michael Milosevic, Laura A Dawson, Angela Scardina, Patricia Fischer, Amy Hacker-Prietz, Robert J Kinders, Lihua Wang, Alice Chen, Sarah Temkin, Naomi Horiba, Lee-Anne Stayner, Lillian L Siu, Nilofer S Azad
BACKGROUND: The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV). METHODS: Patients were treated with veliparib, 40-400mg orally BID on days 1-21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients...
January 18, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28097235/a-patient-derived-xenograft-platform-to-study-brca-deficient-ovarian-cancers
#2
Erin George, Hyoung Kim, Clemens Krepler, Brandon Wenz, Mehran Makvandi, Janos L Tanyi, Eric Brown, Rugang Zhang, Patricia Brafford, Stephanie Jean, Robert H Mach, Yiling Lu, Gordon B Mills, Meenhard Herlyn, Mark Morgan, Xiaochen Zhang, Robert Soslow, Ronny Drapkin, Neil Johnson, Ying Zheng, George Cotsarelis, Katherine L Nathanson, Fiona Simpkins
Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28078645/parp-inhibitors-in-reproductive-system-cancers-current-use-and-developments
#3
REVIEW
Geraldine O'Sullivan Coyne, Alice P Chen, Robert Meehan, James H Doroshow
The repair of DNA damage is a critical cellular process governed by multiple biochemical pathways that are often found to be defective in cancer cells. The poly(ADP-ribose) polymerase (PARP) family of proteins controls response to single-strand DNA breaks by detecting these damaged sites and recruiting the proper factors for repair. Blocking this pathway forces cells to utilize complementary mechanisms to repair DNA damage. While PARP inhibition may not, in itself, be sufficient to cause tumor cell death, inhibition of DNA repair with PARP inhibitors is an effective cytotoxic strategy when it is used in patients who carry other defective DNA-repair mechanisms, such as mutations in the genes BRCA 1 and 2...
January 11, 2017: Drugs
https://www.readbyqxmd.com/read/28069876/targeting-plk1-to-enhance-efficacy-of-olaparib-in-castration-resistant-prostate-cancer
#4
Xiaoqi Liu, Jie Li, Ruixin Wang, Yifan Kong, Meaghan M Broman, Colin Carlock, Long Chen, Zhiguo Li, Elia Farah, Timothy L Ratliff
Olaparib is a FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data has also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors...
January 9, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28055979/-back-to-a-false-normality-new-intriguing-mechanisms-of-resistance-to-parp-inhibitors
#5
REVIEW
Lorena Incorvaia, Francesc Passiglia, Sergio Rizzo, Antonio Galvano, Angela Listì, Nadia Barraco, Rossella Maragliano, Valentina Calò, Clara Natoli, Marcello Ciaccio, Viviana Bazan, Antonio Russo
Several evidences have shown that BRCA mutations increased tumor-cells sensitivity to PARP inhibitors by synthetic lethality leading to an accelerated development of several compounds targeting the PARP enzymes system as anticancer agents for clinical setting. Most of such compounds have been investigated in ovarian and breast cancer, showing promising efficacy in BRCA-mutated patients. Recently clinical studies of PARP-inhibitors have been extended across different tumor types harboring BRCA-mutations, including also "BRCA-like" sporadic tumors with homologous recombination deficiency (HRD)...
December 31, 2016: Oncotarget
https://www.readbyqxmd.com/read/28034904/rad51-mediates-resistance-of-cancer-stem-cells-to-parp-inhibition-in-triple-negative-breast-cancer
#6
Yajing Liu, Monika L Burness, Rachel Martin-Trevino, Joey Guy, Shoumin Bai, Ramdane Harouaka, Michael D Brooks, Li Shang, Alex Fox, Tahra K Luther, April Davis, Trenton L Baker, Justin Colacino, Shawn G Clouthier, Zhi-Ming Shao, Max S Wicha, Suling Liu
INTRODUCTION: PARP inhibitors have shown promising results in early studies for treatment of breast cancer susceptibility gene (BRCA)-deficient breast cancers; however, resistance ultimately develops. Furthermore, the benefit of PARP inhibitors (PARPi) in triple-negative breast cancers (TNBC) remains unknown. Recent evidence indicates that in TNBCs, cells that display "cancer stem cell" properties are resistant to conventional treatments, mediate tumor metastasis, and contribute to recurrence...
December 29, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28006668/design-and-synthesis-of-novel-7-aminosubstituted-pyrido-2-3-b-pyrazines-exhibiting-anti-breast-cancer-activity
#7
Orestis Argyros, Nikolaos Lougiakis, Eva Kouvari, Alexandra Papafotika, Catherine P Raptopoulou, Vassilis Psycharis, Savvas Christoforidis, Nicole Pouli, Panagiotis Marakos, Constantin Tamvakopoulos
Breast cancer (BrCa) remains an unmet medical need despite the revolutionary development of antibody treatments and protein kinase inhibitors. In the current study, a series of novel substituted pyridopyrazine derivatives have been rationally designed and evaluated as multi-kinase inhibitors in the PI3K pathway. The target compounds were prepared from 6-amino-2-picoline, which upon nitration and selective reduction was converted to suitably substituted 6-methyl-7-aminopyrido[2,3-b]pyrazines. Suitable manipulation of the former amines provided the designed analogues, which were then assessed in vitro against several BrCa cell lines using the MTT cytotoxicity assay...
December 12, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27993965/targeting-the-atr-chk1-axis-with-parp-inhibition-results-in-tumor-regression-in-brca-mutant-ovarian-cancer-models
#8
Hyoung Kim, Erin George, Ryan L Ragland, Stavros Rafail, Rugang Zhang, Clemens Krepler, Mark Morgan, Meenhard Herlyn, Eric J Brown, Fiona Simpkins
PURPOSE: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA mutant (BRCAMUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression. EXPERIMENTAL DESIGN: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776) or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell-cycle, genome instability and apoptosis were evaluated in BRCA1/2MUT HGSOC cells...
December 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27958297/delivering-widespread-brca-testing-and-parp-inhibition-to-patients-with-ovarian-cancer
#9
REVIEW
Angela George, Stan Kaye, Susana Banerjee
The treatment of patients with ovarian cancer is rapidly changing following the success of poly [ADP-ribose] polymerase (PARP) inhibitors in clinical trials. Olaparib is the first PARP inhibitor to be approved by the EMA and FDA for BRCA-mutated ovarian cancer. Germ line BRCA mutation status is now established as a predictive biomarker of potential benefit from treatment with a PARP inhibitor; therefore, knowledge of the BRCA status of an individual patient with ovarian cancer is essential, in order to guide treatment decisions...
December 13, 2016: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/27958296/gynaecological-cancer-parp-inhibition-moving-beyond-brca-mutated-disease
#10
David Killock
No abstract text is available yet for this article.
December 13, 2016: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/27902969/rac1-gtp-ase-signals-wnt-beta-catenin-pathway-mediated-integrin-directed-metastasis-associated-tumor-cell-phenotypes-in-triple-negative-breast-cancers
#11
Pradip De, Jennifer H Carlson, Tyler Jepperson, Scooter Willis, Brian Leyland-Jones, Nandini Dey
The acquisition of integrin-directed metastasis-associated (ID-MA) phenotypes by Triple-Negative Breast Cancer (TNBC) cells is caused by an upregulation of the Wnt-beta-catenin pathway (WP). We reported that WP is one of the salient genetic features of TNBC. RAC-GTPases, small G-proteins which transduce signals from cell surface proteins including integrins, have been implicated in tumorigenesis and metastasis by their role in essential cellular functions like motility. The collective percentage of alteration(s) in RAC1 in ER+ve BC was lower as compared to ER-ve BC (35% vs 57%) (brca/tcga/pub2015)...
November 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27884198/use-of-poly-adp-ribose-polymerase-parp-inhibitors-in-cancer-cells-bearing-ddr-defects-the-rationale-for-their-inclusion-in-the-clinic
#12
REVIEW
Aniello Cerrato, Francesco Morra, Angela Celetti
BACKGROUND: DNA damage response (DDR) defects imply genomic instability and favor tumor progression but make the cells vulnerable to the pharmacological inhibition of the DNA repairing enzymes. Targeting cellular proteins like PARPs, which cooperate and complement molecular defects of the DDR process, induces a specific lethality in DDR defective cancer cells and represents an anti-cancer strategy. Normal cells can tolerate the DNA damage generated by PARP inhibition because of an efficient homologous recombination mechanism (HR); in contrast, cancer cells with a deficient HR are unable to manage the DSBs and appear especially sensitive to the PARP inhibitors (PARPi) effects...
November 24, 2016: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/27880910/cdk12-inhibition-reverses-de-novo-and-acquired-parp-inhibitor-resistance-in-brca-wild-type-and-mutated-models-of-triple-negative-breast-cancer
#13
Shawn F Johnson, Cristina Cruz, Ann Katrin Greifenberg, Sofia Dust, Daniel G Stover, David Chi, Benjamin Primack, Shiliang Cao, Andrea J Bernhardy, Rhiannon Coulson, Jean-Bernard Lazaro, Bose Kochupurakkal, Heather Sun, Christine Unitt, Lisa A Moreau, Kristopher A Sarosiek, Maurizio Scaltriti, Dejan Juric, José Baselga, Andrea L Richardson, Scott J Rodig, Alan D D'Andrea, Judith Balmaña, Neil Johnson, Matthias Geyer, Violeta Serra, Elgene Lim, Geoffrey I Shapiro
Although poly(ADP-ribose) polymerase (PARP) inhibitors are active in homologous recombination (HR)-deficient cancers, their utility is limited by acquired resistance after restoration of HR. Here, we report that dinaciclib, an inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 5, and 9, additionally has potent activity against CDK12, a transcriptional regulator of HR. In BRCA-mutated triple-negative breast cancer (TNBC) cells and patient-derived xenografts (PDXs), dinaciclib ablates restored HR and reverses PARP inhibitor resistance...
November 22, 2016: Cell Reports
https://www.readbyqxmd.com/read/27811964/the-poly-adp-ribose-polymerase-inhibitor-veliparib-and-radiation-cause-significant-cell-line-dependent-metabolic-changes-in-breast-cancer-cells
#14
Vijesh J Bhute, Yan Ma, Xiaoping Bao, Sean P Palecek
Breast tumors are characterized into subtypes based on their surface marker expression, which affects their prognosis and treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in clinical trials, both as single agents and in combination with other chemotherapeutics, in several subtypes of breast cancer patients. Here, we used NMR-based metabolomics to probe cell line-specific effects of the PARP inhibitor Veliparib and radiation on metabolism in three breast cancer cell lines...
November 4, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27766838/3d-bioprinting-a-cell-laden-bone-matrix-for-breast-cancer-metastasis-study
#15
Xuan Zhou, Wei Zhu, Margaret Nowicki, Shida Miao, Haitao Cui, Benjamin Holmes, Robert I Glazer, Lijie Grace Zhang
Metastasis is one of the deadliest consequences of breast cancer, with bone being one of the primary sites of occurrence. Insufficient 3D biomimetic models currently exist to replicate this process in vitro. In this study, we developed a biomimetic bone matrix using 3D bioprinting technology to investigate the interaction between breast cancer (BrCa) cells and bone stromal cells (fetal osteoblasts and human bone marrow mesenchymal stem cells (MSCs)). A tabletop stereolithography 3D bioprinter was employed to fabricate a series of bone matrices consisting of osteoblasts or MSCs encapsulated in gelatin methacrylate (GelMA) hydrogel with nanocrystalline hydroxyapatite (nHA)...
November 9, 2016: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/27740936/reduced-pak1-activity-sensitizes-fa-brca-proficient-breast-cancer-cells-to-parp-inhibition
#16
Olga Villamar Cruz, Tatiana Y Prudnikova, Daniela Araiza-Olivera, Carlos Perez-Plasencia, Neil Johnson, Andrea J Bernhardy, Michael Slifker, Catherine Renner, Jonathan Chernoff, Luis E Arias-Romero
Cells that are deficient in homologous recombination, such as those that have mutations in any of the Fanconi Anemia (FA)/BRCA genes, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, FA/BRCA-deficient tumors represent a small fraction of breast cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. The gene encoding the serine-threonine protein kinase p21-activated kinase 1 (PAK1) is amplified and/or overexpressed in several human cancer types including 25-30% of breast tumors...
October 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27716873/the-current-status-of-parp-inhibitors-in-ovarian-cancer
#17
Jennifer McLachlan, Angela George, Susana Banerjee
Recent 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...
October 13, 2016: Tumori
https://www.readbyqxmd.com/read/27708213/resistance-to-parp-inhibitors-by-slfn11-inactivation-can-be-overcome-by-atr-inhibition
#18
Junko Murai, Ying Feng, Guoying K Yu, Yuanbin Ru, Sai-Wen Tang, Yuqiao Shen, Yves Pommier
Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARPI inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between response to talazoparib and Schlafen 11 (SLFN11) expression. Causality was established in four isogenic SLFN11-positive and -negative cell lines and extended to olaparib. Response to the talazoparib-temozolomide combination was also driven by SLFN11 and validated in 36 small cell lung cancer cell lines, and in xenograft models...
September 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27673289/the-status-of-poly-adenosine-diphosphate-ribose-polymerase-parp-inhibitors-in-ovarian-cancer-part-2-extending-the-scope-beyond-olaparib-and-brca1-2-mutations
#19
Rowan E Miller, Jonathan A Ledermann
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown clinical activity in epithelial ovarian cancer, leading both the US Food and Drug Administration (FDA) and the European Medicines Agency to approve olaparib for tumors characterized by BRCA1 and BRCA2 mutations. However, it is becoming increasingly evident that tumors that share molecular features with BRCA-mutant tumors-a concept known as BRCAness-also may exhibit defective homologous recombination DNA repair, and therefore will respond to PARP inhibition...
September 2016: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/27634150/update-on-poly-adp-ribose-polymerase-inhibition-for-ovarian-cancer-treatment
#20
REVIEW
Anselmo Papa, Davide Caruso, Martina Strudel, Silverio Tomao, Federica Tomao
BACKGROUND: Despite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors...
September 15, 2016: Journal of Translational Medicine
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