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https://www.readbyqxmd.com/read/29187880/the-parp-1-inhibitor-olaparib-suppresses-brca1-protein-levels-increases-apoptosis-and-causes-radiation-hypersensitivity-in-brca1-lymphoblastoid-cells
#1
Emma C Bourton, Pia-Amata Ahorner, Piers N Plowman, Sheba Adam Zahir, Hussein Al-Ali, Christopher N Parris
The use of polyADPribose polymerase inhibitors in cancer treatment provides a unique opportunity to target DNA repair processes in cancer cells while leaving normal tissue intact. The PARP-1 enzyme repairs DNA single strand breaks (SSB). Therefore PARP-1 inhibition in BRCA1 negative cancers results in the formation of cytotoxic DNA double strand breaks (DSB) causing synthetic lethality. The use of PARP1 inhibitors is gaining momentum in the treatment of a variety of tumours with BRCA1 involvement including breast, ovarian, pancreatic and prostate cancer...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/29138344/targeting-the-mycn-parp-dna-damage-response-pathway-inneuroendocrine-prostate-cancer
#2
Wei Zhang, Bo Liu, Wenhui Wu, Likun Li, Bradley M Broom, Spyridon M Basourakos, Dimitrios Korentzelos, Yang Luan, Jianxiang Wang, Guang Yang, Sanghee Park, Abul K Azad, Xuhong Cao, Jeri Kim, Paul Corn, Christopher Logothetis, Ana M Aparicio, Arul M Chinnayan, Nora M Navone, Patricia Troncoso, Timothy C Thompson
PURPOSE: We investigated MYCN-regulated molecular pathways in castration-resistant prostate cancer (CRPC) classified by morphological criteria as adenocarcinoma or neuroendocrine to extend the molecular phenotype, establish driver pathways, and identify novel approaches to combination therapy for NEPC. RESULTS: Using comparative bioinformatics analyses of CRPC-Adeno and CRPC-Neuro RNA sequence data from public datasets and a panel of 28 PDX models we identified a MYCN-PARP-DNA damage response (DDR) pathway that is enriched in CRPC with neuroendocrine differentiation (NED) and CRPC-Neuro...
November 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28895177/a-novel-use-for-olaparib-for-treatment-of-metastatic-castration-recurrent-prostate-cancer
#3
Grace A Martin, Adrienne H Chen, Kinjal Parikh
Although mortality from prostate cancer has declined over the past 20 years as a result of early detection and treatment, the 5-year survival rate for men with prostate cancer who develop metastatic disease is only 29%. Current treatment options for metastatic castration-recurrent prostate cancer (mCRPC) are associated with toxicity and a limited durable response; therefore, additional lines of efficacious and minimally toxic therapy are needed. Olaparib, a poly(adenosine 5'-diphosphate) ribose polymerase (PARP) inhibitor, received United States Food and Drug Administration breakthrough therapy designation in January 2016 for the treatment of patients with BRCA1/2 or ATM gene-mutated mCRPC based on results of a compelling phase II trial of olaparib in patients with advanced castration resistant prostate cancer (TOPARP-A)...
September 12, 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/28780018/acute-myeloid-leukemia-after-olaparib-treatment-in-metastatic-castration-resistant-prostate-cancer
#4
Jason Zhu, Matthew Tucker, Endi Wang, Joel S Grossman, Andrew J Armstrong, Daniel J George, Tian Zhang
No abstract text is available yet for this article.
July 14, 2017: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/28663235/immunotherapy-of-prostate-cancer-facts-and-hopes
#5
REVIEW
Marijo Bilusic, Ravi A Madan, James L Gulley
In the last few years, immunotherapy has become an important cancer treatment modality, and although the principles of immunotherapy have evolved over many decades, the FDA approvals of sipuleucel-T and ipilimumab began a new wave in immuno-oncology. Despite the current enthusiasm, it is unlikely that any of the immunotherapeutics alone can dramatically change prostate cancer outcomes, but combination strategies are more promising and provide a reason for optimism. Several completed and ongoing studies have shown that the combination of cancer vaccines or checkpoint inhibitors with different immunotherapeutic agents, hormonal therapy (enzalutamide), radiotherapy (radium 223), DNA-damaging agents (olaparib), or chemotherapy (docetaxel) can enhance immune responses and induce more dramatic, long-lasting clinical responses without significant toxicity...
November 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28540598/parp-inhibitors-in-prostate-cancer
#6
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
#7
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/28500233/nanoformulation-of-olaparib-amplifies-parp-inhibition-and-sensitizes-pten-tp53-deficient-prostate-cancer-to-radiation
#8
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/28450426/analysis-of-circulating-cell-free-dna-identifies-multiclonal-heterogeneity-of-brca2-reversion-mutations-associated-with-resistance-to-parp-inhibitors
#9
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 Pritchard, George Thomas, Scott Tomlins, Karen Knudsen, Christopher J Lord, Charles 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 repair (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 patients with prostate cancer...
September 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28450425/circulating-cell-free-dna-to-guide-prostate-cancer-treatment-with-parp-inhibition
#10
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 more precise patient care are needed in metastatic prostate cancer. We have reported a phase II trial (TOPARP-A) of the PARP inhibitor olaparib in metastatic prostate cancer, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole-exome sequencing of serial circulating cell-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...
September 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28323658/changing-face-of-metastatic-prostate-cancer-the-law-of-diminishing-returns-holds-true
#11
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
https://www.readbyqxmd.com/read/28280302/defective-dna-repair-mechanisms-in-prostate-cancer-impact-of-olaparib
#12
REVIEW
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
https://www.readbyqxmd.com/read/28182994/atm-deficient-colorectal-cancer-cells-are-sensitive-to-the-parp-inhibitor-olaparib
#13
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
https://www.readbyqxmd.com/read/28117679/the-potential-of-targeting-ribosome-biogenesis-in-high-grade-serous-ovarian-cancer
#14
REVIEW
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
https://www.readbyqxmd.com/read/28069876/targeting-plk1-to-enhance-efficacy-of-olaparib-in-castration-resistant-prostate-cancer
#15
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
https://www.readbyqxmd.com/read/27875103/diffusion-weighted-imaging-as-a-treatment-response-biomarker-for-evaluating-bone-metastases-in-prostate-cancer-a-pilot-study
#16
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
https://www.readbyqxmd.com/read/27675112/nanoformulation-of-the-parp-inhibitor-olaparib-enables-radiosensitization-of-a-radiation-resistant-prostate-cancer-model
#17
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
https://www.readbyqxmd.com/read/27600766/evaluation-of-the-radiosensitizing-potency-of-chemotherapeutic-agents-in-prostate-cancer-cells
#18
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...
February 2017: International Journal of Radiation Biology
https://www.readbyqxmd.com/read/27428646/parp-inhibitors-in-clinical-use-induce-genomic-instability-in-normal-human-cells
#19
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
https://www.readbyqxmd.com/read/27426307/combined-inhibition-of-pi3k-and-parp-is-effective-in-the-treatment-of-ovarian-cancer-cells-with-wild-type-pik3ca-genes
#20
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
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