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https://www.readbyqxmd.com/read/28540598/parp-inhibitors-in-prostate-cancer
#1
REVIEW
Praveen Ramakrishnan Geethakumari, Matthew J Schiewer, Karen E Knudsen, Wm Kevin Kelly
The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve "synthetic lethality" in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded "breakthrough designation" to develop the PARPi olaparib in treating this subset of metastatic PCa patients...
June 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28536297/androgen-receptor-inhibitor-induced-brcaness-and-parp-inhibition-are-synthetically-lethal-for-castration-resistant-prostate-cancer
#2
Likun Li, Styliani Karanika, Guang Yang, Jiangxiang Wang, Sanghee Park, Bradley M Broom, Ganiraju C Manyam, Wenhui Wu, Yong Luo, Spyridon Basourakos, Jian H Song, Gary E Gallick, Theodoros Karantanos, Dimitrios Korentzelos, Abul Kalam Azad, Jeri Kim, Paul G Corn, Ana M Aparicio, Christopher J Logothetis, Patricia Troncoso, Timothy Heffernan, Carlo Toniatti, Hyun-Sung Lee, Ju-Seog Lee, Xuemei Zuo, Wenjun Chang, Jianhua Yin, Timothy C Thompson
Cancers with loss-of-function mutations in BRCA1 or BRCA2 are deficient in the DNA damage repair pathway called homologous recombination (HR), rendering these cancers exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors. This functional state and therapeutic sensitivity is referred to as "BRCAness" and is most commonly associated with some breast cancer types. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only ~20% of prostate cancer patients...
May 23, 2017: Science Signaling
https://www.readbyqxmd.com/read/28525389/biological-and-clinical-evidence-for-somatic-mutations-in-brca1-and-brca2-as-predictive-markers-for-olaparib-response-in-high-grade-serous-ovarian-cancers-in-the-maintenance-setting
#3
Brian A Dougherty, Zhongwu Lai, Darren R Hodgson, Maria C M Orr, Matthew Hawryluk, James Sun, Roman Yelensky, Stuart K Spencer, Jane D Robertson, Tony W Ho, Anitra Fielding, Jonathan A Ledermann, J Carl Barrett
To gain a better understanding of the role of somatic mutations in olaparib response, next-generation sequencing (NGS) of BRCA1 and BRCA2 was performed as part of a planned retrospective analysis of tumors from a randomized, double-blind, Phase II trial (Study 19; D0810C00019; NCT00753545) in 265 patients with platinum-sensitive high-grade serous ovarian cancer. BRCA1/2 loss-of-function mutations were found in 55% (114/209) of tumors, were mutually exclusive, and demonstrated high concordance with Sanger-sequenced germline mutations in matched blood samples, confirming the accuracy (97%) of tumor BRCA1/2 NGS testing...
May 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28512243/plk1-phosphorylation-of-mre11-antagonizes-the-dna-damage-response
#4
Zhiguo Li, Jie Li, Yifan Kong, Shan Yan, Nihal Ahmad, Xiaoqi Liu
The mitotic kinase Plk1 contributes to the DNA damage response (DDR) by targeting multiple factors downstream of the core responder kinase ATM/ATR. In this study, we show that Plk1 also phosphorylates key factors upstream of ATM/ATR and regulates their DDR-related functions. Plk1 phosphorylated Mre11, a component of the Mre11/Rad50/Nbs1 (MRN) complex, at serine 649 (S649) during DDR. Phosphorylation of Mre11-S649 by Plk1 primed subsequent CK2-mediated phosphorylation at Mre11-serine 688 (S688). Phosphorylation of Mre11 at S649/S688 inhibited loading of the MRN complex to damaged DNA, leading to both premature DNA damage checkpoint termination and inhibition of DNA repair...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28508305/recent-advances-in-targeting-dna-repair-pathways-for-the-treatment-of-ovarian-cancer-and-their-clinical-relevance
#5
REVIEW
Katsutoshi Oda, Michihiro Tanikawa, Kenbun Sone, Mayuyo Mori-Uchino, Yutaka Osuga, Tomoyuki Fujii
Poly (ADP-ribose) polymerase (PARP) inhibitors have attracted much attention as one of the major molecular-targeted therapeutics for inhibiting DNA damage response. The PARP inhibitor, olaparib, has been clinically applied for treating certain recurrent ovarian cancer patients with BRCA1/2 mutations in Europe and the United States. It was also designated on 24 March 2017 as an orphan drug in Japan for similar clinical indications. In this review, we discuss (i) the prevalence of BRCA1/2 mutations in ovarian cancer, (ii) clinical trials of PARP inhibitors in ovarian cancer, (iii) genetic counseling for hereditary breast and ovarian cancer patients, and (iv) non-BRCA genes that may be associated with homologous recombination deficiency...
May 15, 2017: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28500233/nanoformulation-of-olaparib-amplifies-parp-inhibition-and-sensitizes-pten-tp53-deficient-prostate-cancer-to-radiation
#6
Anne L van de Ven, Shifalika Tangutoori, Paige Baldwin, Ju Qiao, Codi Gharagouzloo, Nina Seitzer, John G Clohessy, G Mike Makrigiorgos, Robert Cormack, Pier Paolo Pandolfi, Srinivas Sridhar
The use of PARP inhibitors in combination with radiation therapy is a promising strategy to locally enhance DNA-damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation-sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of Olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone...
May 12, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28490518/chk1-inhibition-in-small-cell-lung-cancer-produces-single-agent-activity-in-biomarker-defined-disease-subsets-and-combination-activity-with-cisplatin-or-olaparib
#7
Triparna Sen, Pan Tong, C Allison Stewart, Sandra Cristea, Aly Valliani, David S Shames, Abena Redwood, Youhong Fan, Lerong Li, Bonnie S Glisson, John Minna, Julien Sage, Don L Gibbons, Helen Piwnica-Worms, John Heymach, Jing Wang, Lauren Averett Byers
Effective targeted therapies for small cell lung cancer (SCLC), the most aggressive form of lung cancer, remain urgently needed. Here we report evidence of preclinical efficacy evoked by targeting the overexpressed cell cycle checkpoint kinase CHK1 in SCLC. Our studies employed RNAi-mediated attenuation or pharmacological blockade with the novel second-generation CHK1 inhibitor prexasertib (LY2606368), currently in clinical trials. In SCLC models in vitro and in vivo, LY2606368 exhibited strong single-agent efficacy, augmented the effects of cisplatin or the PARP inhibitor olaparib, and improved the response of platinum-resistant models...
May 10, 2017: Cancer Research
https://www.readbyqxmd.com/read/28487110/nf90-regulates-parp1-mrna-stability-in-hepatocellular-carcinoma
#8
Dan Song, Huixing Huang, Juanjuan Wang, Yahui Zhao, Xiaoding Hu, Funan He, Long Yu, Jiaxue Wu
Poly (ADP-ribose) polymerase 1 (PARP1) is an ADP- ribosylation enzyme and plays important roles in a variety of cellular processes, including DNA damage response and tumor development. However, the post-transcriptional regulation of PARP1 remains largely unknown. In this study, we identified that the mRNA of PARP1 is associated with nuclear factor 90 (NF90) by RNA immunoprecipitation plus sequencing (RIP-seq) assay. The mRNA and protein levels of PARP1 are dramatically decreased in NF90-depleted cells, and NF90 stabilizes PARP1's mRNA through its 3'UTR...
June 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28482906/foxm1-expression-is-significantly-associated-with-chemotherapy-resistance-and-adverse-prognosis-in-non-serous-epithelial-ovarian-cancer-patients
#9
Renata A Tassi, Paola Todeschini, Eric R Siegel, Stefano Calza, Paolo Cappella, Laura Ardighieri, Moris Cadei, Mattia Bugatti, Chiara Romani, Elisabetta Bandiera, Laura Zanotti, Laura Tassone, Donatella Guarino, Concetta Santonocito, Ettore D Capoluongo, Luca Beltrame, Eugenio Erba, Sergio Marchini, Maurizio D'Incalci, Carla Donzelli, Alessandro D Santin, Sergio Pecorelli, Enrico Sartori, Eliana Bignotti, Franco Odicino, Antonella Ravaggi
BACKGROUND: Epithelial ovarian cancer (EOC) is a spectrum of different diseases, which makes their treatment a challenge. Forkhead box M1 (FOXM1) is an oncogene aberrantly expressed in many solid cancers including serous EOC, but its role in non-serous EOCs remains undefined. We examined FOXM1 expression and its correlation to prognosis across the three major EOC subtypes, and its role in tumorigenesis and chemo-resistance in vitro. METHODS: Gene signatures were generated by microarray for 14 clear-cell and 26 endometrioid EOCs, and 15 normal endometrium snap-frozen biopsies...
May 8, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28471727/safety-and-clinical-activity-of-the-programmed-death-ligand-1-inhibitor-durvalumab-in-combination-with-poly-adp-ribose-polymerase-inhibitor-olaparib-or-vascular-endothelial-growth-factor-receptor-1-3-inhibitor-cediranib-in-women-s-cancers-a-dose-escalation
#10
Jung-Min Lee, Ashley Cimino-Mathews, Cody J Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M Annunziata, Liang Cao, Maria I Harrell, Elizabeth M Swisher, Nicole Houston, Dana-Adriana Botesteanu, Janis M Taube, Elizabeth Thompson, Aleksandra Ogurtsova, Haiying Xu, Jeffers Nguyen, Tony W Ho, William D Figg, Elise C Kohn
Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable and active in recurrent women's cancers. Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations...
May 4, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28462496/synthetic-lethal-targeting-of-rnf20-through-parp1-silencing-and-inhibition
#11
Brent J Guppy, Kirk J McManus
PURPOSE: The identification of novel therapeutic targets that exploit the aberrant genetics driving oncogenesis is critical to better combat cancer. RNF20 is somatically altered in numerous cancers, and its diminished expression drives genome instability, a driving factor of oncogenesis. Accordingly, we sought to determine whether PARP1 silencing and inhibition could preferentially kill RNF20-deficient cells using a synthetic lethal strategy. METHODS: RNF20 and PARP1 were silenced using RNAi-based approaches...
May 1, 2017: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/28454547/parp1-expression-drives-the-synergistic-antitumor-activity-of-trabectedin-and-parp1-inhibitors-in-sarcoma-preclinical-models
#12
Ymera Pignochino, Federica Capozzi, Lorenzo D'Ambrosio, Carmine Dell'Aglio, Marco Basiricò, Marta Canta, Annalisa Lorenzato, Francesca Vignolo Lutati, Sandra Aliberti, Erica Palesandro, Paola Boccone, Danilo Galizia, Sara Miano, Giulia Chiabotto, Lucia Napione, Loretta Gammaitoni, Dario Sangiolo, Maria Serena Benassi, Barbara Pasini, Giovanna Chiorino, Massimo Aglietta, Giovanni Grignani
BACKGROUND: Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death...
April 28, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28454122/olaparib-in-combination-with-irinotecan-cisplatin-and-mitomycin-c-in-patients-with-advanced-pancreatic-cancer
#13
Mark Yarchoan, Melinda C Myzak, Burles A Johnson Iii, Ana De Jesus-Acosta, Dung T Le, Elizabeth M Jaffee, Nilofer S Azad, Ross C Donehower, Lei Zheng, Paul E Oberstein, Robert L Fine, Daniel A Laheru, Michael Goggins
BACKGROUND: Olaparib is an oral inhibitor of polyadenosine 5'-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: In this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m2 on days 1 and 8 and cisplatin 25 mg/m2 on days 1 and 8 of a 28-day cycle (olaparib plus IC)...
April 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28454085/baseline-clinical-predictors-of-antitumor-response-to-the-parp-inhibitor-olaparib-in-germline-brca1-2-mutated-patients-with-advanced-ovarian-cancer
#14
Saeed Rafii, Charlie Gourley, Rajiv Kumar, Elena Geuna, Joo Ern Ang, Tzyvia Rye, Lee-May Chen, Ronnie Shapira-Frommer, Michael Friedlander, Ursula Matulonis, Jacques De Greve, Amit M Oza, Susana Banerjee, L Rhoda Molife, Martin E Gore, Stan B Kaye, Timothy A Yap
BACKGROUND: The PARP inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer. However, antitumor responses are observed in only approximately 40% of patients and the impact of baseline clinical factors on response to treatment remains unclear. Although platinum sensitivity has been suggested as a marker of response to PARP inhibitors, patients with platinum-resistant disease still respond to olaparib...
April 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28450426/analysis-of-circulating-cell-free-dna-identifies-multi-clonal-heterogeneity-of-brca2-reversion-mutations-associated-with-resistance-to-parp-inhibitors
#15
David Quigley, Joshi J Alumkal, Alexander W Wyatt, Vishal Kothari, Adam Foye, Paul Lloyd, Rahul Aggarwal, Won Kim, Eric Lu, Jacob Schwartzman, Kevin Beja, Matti Annala, Rajdeep Das, Morgan Diolaiti, Colin C Pritchard, George V Thomas, Scott A Tomlins, Karen E Knudsen, Christopher J Lord, Charles J Ryan, Jack Youngren, Tomasz M Beer, Alan Ashworth, Eric J Small, Felix Y Feng
Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination (HRR) such as BRCA2. HRR defects confer synthetic lethality to PARP inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by BRCA2 mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify BRCA2 reversion mutations associated with olaparib and talazoparib resistance in prostate cancer patients...
April 27, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28450425/circulating-free-dna-to-guide-prostate-cancer-treatment-with-parp-inhibition
#16
Jane Goodall, Joaquin Mateo, Wei Yuan, Helen Mossop, Nuria Porta, Susana Miranda, Raquel Perez-Lopez, David Dolling, Dan R Robinson, Shahneen Sandhu, Gemma Fowler, Berni Ebbs, Penny Flohr, George Seed, Daniel Nava Rodrigues, Gunther Boysen, Claudia Bertan, Mark Atkin, Matthew Clarke, Mateus Crespo, Ines Figueiredo, Ruth Riisnaes, Semini Sumanasuriya, Pasquale Rescigno, Zafeiris Zafeiriou, Adam Sharp, Nina Tunariu, Diletta Bianchini, Alexa Gillman, Christopher J Lord, Emma Hall, Arul M Chinnaiyan, Suzanne Carreira, Johann S de Bono
Biomarkers for a more precise patient care are needed in metastatic prostate cancer (mPC). We have reported a Phase II trial (TOPARP-A) of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib in mPC, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole exome sequencing of serial circulating-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0...
April 27, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28415784/misregulation-of-dna-damage-repair-pathways-in-hpv-positive-head-and-neck-squamous-cell-carcinoma-contributes-to-cellular-radiosensitivity
#17
Catherine M Nickson, Parisa Moori, Rachel J Carter, Carlos P Rubbi, Jason L Parsons
Patients with human papillomavirus type 16 (HPV)-associated oropharyngeal squamous cell carcinomas (OPSCC) display increased sensitivity to radiotherapy and improved survival rates in comparison to HPV-negative forms of the disease. However the cellular mechanisms responsible for this characteristic difference are unclear. Here, we have investigated the contribution of DNA damage repair pathways to the in vitro radiosensitivity of OPSCC cell lines. We demonstrate that two HPV-positive OPSCC cells are indeed more radiosensitive than two HPV-negative OPSCC cells, which correlates with reduced efficiency for the repair of ionising radiation (IR)-induced DNA double strand breaks (DSB)...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28398198/functional-and-mutational-landscapes-of-brca1-for-homology-directed-repair-and-therapy-resistance
#18
Rachel W Anantha, Srilatha Simhadri, Tzeh Keong Foo, Susanna Miao, Jingmei Liu, Zhiyuan Shen, Shridar Ganesan, Bing Xia
BRCA1 plays a critical role in homology-directed repair (HDR) of DNA double strand breaks, and the repair defect of BRCA1-mutant cancer cells is being targeted with platinum drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. We have employed relatively simple and sensitive assays to determine the function of BRCA1 variants or mutants in two HDR mechanisms, homologous recombination (HR) and single strand annealing (SSA), and in conferring resistance to cisplatin and olaparib in human cancer cells. Our results define the functionality of the top 22 patient-derived BRCA1 missense variants and the contribution of different domains of BRCA1 and its E3 ubiquitin ligase activity to HDR and drug resistance...
April 11, 2017: ELife
https://www.readbyqxmd.com/read/28395540/olaparib-for-the-treatment-of-breast-cancer
#19
Marie Robert, Jean-Sébastien Frenel, Carole Gourmelon, Anne Patsouris, Paule Augereau, Mario Campone
Basal-like breast cancer is characterized by being triple negative and aggressive. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found in 11 to 42% of these tumors, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors exploit this deficiency through a synthetic lethality and are considered as promising anticancer therapies, especially in patients harboring BRCA1 or BRCA 2 mutations. Areas covered: Olaparib is one of the most widely investigated PARP inhibitors...
April 21, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28394338/parp-inhibitors-enhance-replication-stress-and-cause-mitotic-catastrophe-in-mycn-dependent-neuroblastoma
#20
V Colicchia, M Petroni, G Guarguaglini, F Sardina, M Sahún-Roncero, M Carbonari, B Ricci, C Heil, C Capalbo, F Belardinilli, A Coppa, G Peruzzi, I Screpanti, P Lavia, A Gulino, G Giannini
High-risk and MYCN-amplified neuroblastomas are among the most aggressive pediatric tumors. Despite intense multimodality therapies, about 50% of these patients succumb to their disease, making the search for effective therapies an absolute priority. Due to the important functions of poly (ADP-ribose) polymerases, PARP inhibitors have entered the clinical settings for cancer treatment and are being exploited in a variety of preclinical studies and clinical trials. PARP inhibitors based combination schemes have also been tested in neuroblastoma preclinical models with encouraging results...
April 10, 2017: Oncogene
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