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Olaparib prostat

Ulka N Vaishampayan
PURPOSE OF REVIEW: Prostate cancer presents with a multitude of faces. It ranges from localized cancers staying quiescent for many years during active surveillance to the raging diffuse liver metastases causing terminal disease. The incidence of metastatic disease is increasing. This review will highlight some of the recent developments as well as ongoing challenges of managing advanced prostate cancer. RECENT FINDINGS: Significant strides are being made in managing metastatic prostate cancer...
March 18, 2017: Current Opinion in Oncology
Francesca De Felice, Vincenzo Tombolini, Francesco Marampon, Angela Musella, Claudia Marchetti
The field of prostate oncology has continued to change dramatically. It has truly become a field that is intensely linked to molecular genetic alterations, especially DNA-repair defects. Germline breast cancer 1 gene (BRCA1) and breast cancer 2 gene (BRCA2) mutations are implicated in the highest risk of prostate cancer (PC) predisposition and aggressiveness. Poly adenosine diphosphate ribose polymerase (PARP) proteins play a key role in DNA repair mechanisms and represent a valid target for new therapies. Olaparib is an oral PARP inhibitor that blocks DNA repair pathway and coupled with BRCA mutated-disease results in tumor cell death...
2017: Drug Design, Development and Therapy
Chen Wang, Nicholas Jette, Daniel Moussienko, D Gwyn Bebb, Susan P Lees-Miller
The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors...
April 2017: Translational Oncology
Shunfei Yan, Daniel Frank, Jinbae Son, Katherine M Hannan, Ross D Hannan, Keefe T Chan, Richard B Pearson, Elaine Sanij
Overall survival for patients with ovarian cancer (OC) has shown little improvement for decades meaning new therapeutic options are critical. OC comprises multiple histological subtypes, of which the most common and aggressive subtype is high-grade serous ovarian cancer (HGSOC). HGSOC is characterized by genomic structural variations with relatively few recurrent somatic mutations or dominantly acting oncogenes that can be targeted for the development of novel therapies. However, deregulation of pathways controlling homologous recombination (HR) and ribosome biogenesis has been observed in a high proportion of HGSOC, raising the possibility that targeting these basic cellular processes may provide improved patient outcomes...
January 20, 2017: International Journal of Molecular Sciences
Jie Li, Ruixin Wang, Yifan Kong, Meaghan M Broman, Colin Carlock, Long Chen, Zhiguo Li, Elia Farah, Timothy L Ratliff, Xiaoqi Liu
Olaparib is an 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 have 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...
March 2017: Molecular Cancer Therapeutics
Raquel Perez-Lopez, Joaquin Mateo, Helen Mossop, Matthew D Blackledge, David J Collins, Mihaela Rata, Veronica A Morgan, Alison Macdonald, Shahneen Sandhu, David Lorente, Pasquale Rescigno, Zafeiris Zafeiriou, Diletta Bianchini, Nuria Porta, Emma Hall, Martin O Leach, Johann S de Bono, Dow-Mu Koh, Nina Tunariu
Purpose To determine the usefulness of whole-body diffusion-weighted imaging (DWI) to assess the response of bone metastases to treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). Materials and Methods A phase II prospective clinical trial of the poly-(adenosine diphosphate-ribose) polymerase inhibitor olaparib in mCRPC included a prospective magnetic resonance (MR) imaging substudy; the study was approved by the institutional research board, and written informed consent was obtained...
April 2017: Radiology
P Baldwin, A L Van De Ven, N Seitzer, S Clohessy, R A Cormack, M Makrigiorgos, P P Pandolfi, S Sridhar
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
Colin Rae, Robert J Mairs
PURPOSE: Despite recent advances in the treatment of metastatic prostate cancer, survival rates are low and treatment options are limited to chemotherapy and hormonal therapy. Although ionizing radiation is used to treat localized and metastatic prostate cancer, the most efficient use of radiotherapy is yet to be defined. Our purpose was to determine in vitro the potential benefit to be gained by combining radiation treatment with cytotoxic drugs. MATERIALS AND METHODS: Inhibitors of DNA repair and heat shock protein 90 and an inducer of oxidative stress were evaluated in combination with X-radiation for their capacity to reduce clonogenic survival and delay the growth of multicellular tumor spheroids...
October 3, 2016: International Journal of Radiation Biology
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
Dong Wang, Chengbo Li, Yuan Zhang, Min Wang, Nan Jiang, Lin Xiang, Ting Li, Thomas M Roberts, Jean J Zhao, Hailing Cheng, Pixu Liu
OBJECTIVE: Combined inhibition of PI3K and PARP has been shown to be effective in the treatment of preclinical models of breast cancer and prostate cancer independent of BRCA or PIK3CA mutational status. However, the knowledge about this combination treatment in ovarian cancer is limited. The aim of this study was to evaluate the therapeutic effect of PI3K inhibitor BKM120 and PARP inhibitor Olaparib on ovarian cancer cell lines bearing wild-type PIK3CA genes. METHODS: We exposed three wild-type PIK3CA ovarian cancer cell lines to a PI3K inhibitor BKM120 and/or a PARP inhibitor Olaparib...
September 2016: Gynecologic Oncology
Mallika Dhawan, Charles J Ryan, Alan Ashworth
UNLABELLED: : Advances in DNA sequencing technology have created a wealth of information regarding the genomic landscape of prostate cancer. It had been thought that BRCA1 and BRCA2 mutations were associated with only a small fraction of prostate cancer cases. However, recent genomic analysis has revealed that germline or somatic inactivating mutations in BRCA1 or BRCA2, or other genes involved in the homologous recombination (HR) pathway of DNA repair collectively occur in as much as 20%-25% of advanced prostate cancers...
August 2016: Oncologist
Samir S Taneja
No abstract text is available yet for this article.
April 2016: Journal of Urology
Wim P J Witjes
No abstract text is available yet for this article.
July 2016: European Urology
Mathias Tesson, Colin Rae, Colin Nixon, John W Babich, Robert J Mairs
OBJECTIVES: Despite recent advances in the treatment of metastatic prostate cancer, survival rates are low and treatment options are limited to chemotherapy and hormonal therapy. (131) I-MIP-1095 is a recently developed prostate-specific membrane antigen (PSMA)-targeting, small molecular weight radiopharmaceutical which has anti-tumour activity as a single agent. Our purpose was to determine in vitro the potential benefit to be gained by combining (131) I-MIP-1095 with cytotoxic drug treatments...
July 2016: Journal of Pharmacy and Pharmacology
Dong Wang, Min Wang, Nan Jiang, Yuan Zhang, Xing Bian, Xiaoqing Wang, Thomas M Roberts, Jean J Zhao, Pixu Liu, Hailing Cheng
Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent...
March 15, 2016: Oncotarget
(no author information available yet)
In the phase II TOPARP-A clinical trial, patients with metastatic castrate-resistant prostate cancer who were treated with the PARP inhibitor olaparib lived nearly three times longer without their cancer worsening if their tumors had mutations in at least one of 12 DNA repair genes. However, physicians say that a larger trial is needed to confirm olaparib's effectiveness against the disease before they start routinely sequencing tumors and prescribing the drug.
January 2016: Cancer Discovery
Joaquin Mateo, Suzanne Carreira, Shahneen Sandhu, Susana Miranda, Helen Mossop, Raquel Perez-Lopez, Daniel Nava Rodrigues, Dan Robinson, Aurelius Omlin, Nina Tunariu, Gunther Boysen, Nuria Porta, Penny Flohr, Alexa Gillman, Ines Figueiredo, Claire Paulding, George Seed, Suneil Jain, Christy Ralph, Andrew Protheroe, Syed Hussain, Robert Jones, Tony Elliott, Ursula McGovern, Diletta Bianchini, Jane Goodall, Zafeiris Zafeiriou, Chris T Williamson, Roberta Ferraldeschi, Ruth Riisnaes, Bernardette Ebbs, Gemma Fowler, Desamparados Roda, Wei Yuan, Yi-Mi Wu, Xuhong Cao, Rachel Brough, Helen Pemberton, Roger A'Hern, Amanda Swain, Lakshmi P Kunju, Rosalind Eeles, Gerhardt Attard, Christopher J Lord, Alan Ashworth, Mark A Rubin, Karen E Knudsen, Felix Y Feng, Arul M Chinnaiyan, Emma Hall, Johann S de Bono
BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib. METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day...
October 29, 2015: New England Journal of Medicine
Giovanna Sociali, Lauretta Galeno, Marco Daniele Parenti, Alessia Grozio, Inga Bauer, Mario Passalacqua, Silvia Boero, Alessandra Donadini, Enrico Millo, Marta Bellotti, Laura Sturla, Patrizia Damonte, Alessandra Puddu, Claudia Ferroni, Greta Varchi, Claudio Franceschi, Alberto Ballestrero, Alessandro Poggi, Santina Bruzzone, Alessio Nencioni, Alberto Del Rio
The NAD(+)-dependent sirtuin SIRT6 is highly expressed in human breast, prostate, and skin cancer where it mediates resistance to cytotoxic agents and prevents differentiation. Thus, SIRT6 is an attractive target for the development of new anticancer agents to be used alone or in combination with chemo- or radiotherapy. Here we report on the identification of novel quinazolinedione compounds with inhibitory activity on SIRT6. As predicted based on SIRT6's biological functions, the identified new SIRT6 inhibitors increase histone H3 lysine 9 acetylation, reduce TNF-╬▒ production and increase glucose uptake in cultured cells...
September 18, 2015: European Journal of Medicinal Chemistry
(no author information available yet)
Data from the phase II TOPARP-A clinical trial indicate that men with metastatic castration-resistant prostate cancer are more likely to respond to the PARP inhibitor olaparib if they have mutations in DNA damage repair genes. The study provides the first data supporting molecular stratification for patients with this disease.
June 2015: Cancer Discovery
Shifalika Tangutoori, Paige Baldwin, Srinivas Sridhar
Personalized medicine seeks to utilize targeted therapies with increased selectivity and efficacy in preselected patient cohorts. One such molecularly targeted therapy is enabled by inhibiting the enzyme poly(ADP-ribose) polymerase (PARP) by small molecule inhibitors in tumors which have a defect in the homologous DNA recombination pathway, most characteristically due to BRCA mutations. Olaparib, a highly potent PARP inhibitor, has recently been the approved for ovarian cancer therapy by the FDA and European commission in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with BRCA1 or BRCA2 mutations...
May 2015: Maturitas
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