Only in Titles

Search results for: AZD3514

paperclip

#33402104   2021/01/05 To Up

Assessment of various continual reassessment method models for dose-escalation phase 1 oncology clinical trials: using real clinical data and simulation studies.

The continual reassessment method (CRM) identifies the maximum tolerated dose (MTD) more efficiently and identifies the true MTD more frequently compared to standard methods such as the 3 + 3 method. An initial estimate of the dose-toxicity relationship (prior skeleton) is required, and there is limited guidance on how to select this. Previously, we compared the CRM with six different skeletons to the 3 + 3 method by conducting post-hoc analysis on a phase 1 oncology study (AZD3514), each CRM model reduced the number of patients allocated to suboptimal and toxic doses. This manuscript extends this work by assessing the ability of the 3 + 3 method and the CRM with different skeletons in determining the true MTD of various "true" dose-toxicity relationships.
G D James, S Symeonides, J Marshall, J Young, G Clack

2985 related Products with: Assessment of various continual reassessment method models for dose-escalation phase 1 oncology clinical trials: using real clinical data and simulation studies.

100Tests

Related Pathways

paperclip

#30232143   2018/09/19 To Up

Androgen Receptor Inhibitor Enhances the Antitumor Effect of PARP Inhibitor in Breast Cancer Cells by Modulating DNA Damage Response.

The androgen receptor (AR) is expressed in 60%-70% of breast cancers regardless of estrogen receptor status, and has been proposed as a therapeutic target in breast cancers that retain AR. In this study, the authors aimed to investigate a new treatment strategy using a novel AR inhibitor AZD3514 in breast cancer. AZD3514 alone had a minimal antiproliferative effect on most breast cancer cell lines irrespective of AR expression level, but it downregulated the expressions of DNA damage response (DDR) molecules, including ATM and chk2, which resulted in the accumulation of damaged DNA in some breast cancer cells. Furthermore, AZD3514 enhanced cellular sensitivity to a PARP inhibitor olaparib by blocking the DDR pathway in breast cancer cells. Furthermore, the downregulation of NKX3.1 expression in MDA-MB-468 cells by AZD3514 occurred in parallel with the suppression of ATM-chk2 axis activation, and the suppression of NKX3.1 by AZD3514 was found to result from AZD3514-induced TOPORS upregulation and a resultant increase in NKX3.1 degradation. The study shows posttranslational regulation of NKX3.1 via TOPORS upregulation by AZD3514-induced ATM inactivation-increased olaparib sensitivity in AR-positive and TOPORS-expressing breast cancer cells, and suggests the antitumor effect of AZD3514/olaparib cotreatment is caused by compromised DDR activity in breast cancer cell lines and in a xenograft model. These results provide a rationale for future clinical trials of olaparib/AR inhibitor combination treatment in breast cancer.
Ahrum Min, Hyemin Jang, Seongyeong Kim, Kyung-Hun Lee, Debora Keunyoung Kim, Koung Jin Suh, Yaewon Yang, Paul Elvin, Mark J O'Connor, Seock-Ah Im

2078 related Products with: Androgen Receptor Inhibitor Enhances the Antitumor Effect of PARP Inhibitor in Breast Cancer Cells by Modulating DNA Damage Response.

8 inhibitors10mg5mg100uL10mg96T5 ml100 ul25 mg1 ml5mg

Related Pathways

paperclip

#27581751   2016/08/31 To Up

Continual reassessment method for dose escalation clinical trials in oncology: a comparison of prior skeleton approaches using AZD3514 data.

The continual reassessment method (CRM) requires an underlying model of the dose-toxicity relationship ("prior skeleton") and there is limited guidance of what this should be when little is known about this association. In this manuscript the impact of applying the CRM with different prior skeleton approaches and the 3 + 3 method are compared in terms of ability to determine the true maximum tolerated dose (MTD) and number of patients allocated to sub-optimal and toxic doses.
Gareth D James, Stefan N Symeonides, Jayne Marshall, Julia Young, Glen Clack

2059 related Products with: Continual reassessment method for dose escalation clinical trials in oncology: a comparison of prior skeleton approaches using AZD3514 data.



Related Pathways

paperclip

Error loading info... Pleas try again later.
paperclip

#26876616   2016/02/11 To Up

The value of integrating pre-clinical data to predict nausea and vomiting risk in humans as illustrated by AZD3514, a novel androgen receptor modulator.

Nausea and vomiting are components of a complex mechanism that signals food avoidance and protection of the body against the absorption of ingested toxins. This response can also be triggered by pharmaceuticals. Predicting clinical nausea and vomiting liability for pharmaceutical agents based on pre-clinical data can be problematic as no single animal model is a universal predictor. Moreover, efforts to improve models are hampered by the lack of translational animal and human data in the public domain. AZD3514 is a novel, orally-administered compound that inhibits androgen receptor signaling and down-regulates androgen receptor expression. Here we have explored the utility of integrating data from several pre-clinical models to predict nausea and vomiting in the clinic. Single and repeat doses of AZD3514 resulted in emesis, salivation and gastrointestinal disturbances in the dog, and inhibited gastric emptying in rats after a single dose. AZD3514, at clinically relevant exposures, induced dose-responsive "pica" behaviour in rats after single and multiple daily doses, and induced retching and vomiting behaviour in ferrets after a single dose. We compare these data with the clinical manifestation of nausea and vomiting encountered in patients with castration-resistant prostate cancer receiving AZD3514. Our data reveal a striking relationship between the pre-clinical observations described and the experience of nausea and vomiting in the clinic. In conclusion, the emetic nature of AZD3514 was predicted across a range of pre-clinical models, and the approach presented provides a valuable framework for predicition of clinical nausea and vomiting.
Claire Grant, Lorna Ewart, Daniel Muthas, Damian Deavall, Simon A Smith, Glen Clack, Pete Newham

1588 related Products with: The value of integrating pre-clinical data to predict nausea and vomiting risk in humans as illustrated by AZD3514, a novel androgen receptor modulator.

100ug100ul100ug100ug100ul50 ug 5mg1 ml100ul100ug100.00 ul200ug

Related Pathways

paperclip

#25920479   2015/04/30 To Up

AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer - results of two parallel first-in-human phase I studies.

AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD).
A Omlin, R J Jones, R van der Noll, T Satoh, M Niwakawa, S A Smith, J Graham, M Ong, R D Finkelman, J H M Schellens, A Zivi, M Crespo, R Riisnaes, D Nava-Rodrigues, M D Malone, C Dive, R Sloane, D Moore, J J Alumkal, A Dymond, P A Dickinson, M Ranson, G Clack, J de Bono, T Elliott

2810 related Products with: AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer - results of two parallel first-in-human phase I studies.

100 μg20 100 μg100 μg100 μg100 μg 100ul

Related Pathways

paperclip

#25708954   2015/02/21 To Up

Battling resistance mechanisms in antihormonal prostate cancer treatment: Novel agents and combinations.

Prostate cancer (PCa) is a hormone-sensitive disease. Androgen deprivation therapy lowers serum testosterone levels (castration) or blocks the androgen receptor (AR) ligand-binding domain. Especially in metastatic disease, hormonal therapy has been able to delay disease progression, reduce symptoms, and improve overall survival. Despite subsequent disease progression and development of castration resistance, PCa remains AR driven. Secondary hormonal treatments such as abiraterone acetate or enzalutamide have demonstrated increased overall survival. However, new resistance mechanisms to these agents have been identified, and systemic chemotherapy is still needed especially in fast-progressing castration-resistant PCa. Several promising androgen synthesis inhibitors (orteronel and galeterone), AR inhibitors (ARN-509, EPI-001, AZD3514, and ODM-201), and heat shock protein modulators (AT11387, 17-DMAG, STA-9090, and OGX-427) are currently under investigation. The wide variety in upcoming systemic agents underlines the molecular heterogeneity of castration-resistant PCa. This article reviews antihormonal therapy in PCa and resistance mechanisms and focuses on novel and upcoming agents currently in clinical testing.
Daan Joost De Maeseneer, Charles Van Praet, Nicolaas Lumen, Sylvie Rottey

2853 related Products with: Battling resistance mechanisms in antihormonal prostate cancer treatment: Novel agents and combinations.



Related Pathways

paperclip

Error loading info... Pleas try again later.
paperclip

#23861347   2013/07/16 To Up

AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo.

Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation.
Sarah A Loddick, Sarah J Ross, Andrew G Thomason, David M Robinson, Graeme E Walker, Tom P J Dunkley, Sandra R Brave, Nicola Broadbent, Natalie C Stratton, Dawn Trueman, Elizabeth Mouchet, Fadhel S Shaheen, Vivien N Jacobs, Marie Cumberbatch, Joanne Wilson, Rhys D O Jones, Robert H Bradbury, Alfred Rabow, Luke Gaughan, Chris Womack, Simon T Barry, Craig N Robson, Susan E Critchlow, Stephen R Wedge, A Nigel Brooks

1842 related Products with: AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo.

100ug50 ug 100ul2 Pieces/Box5mg0.1 mg100ul100ug100ug50 ug 50 ug 100ug

Related Pathways

paperclip

#23466225   2013/02/21 To Up

Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer.

Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
Robert H Bradbury, David G Acton, Nicola L Broadbent, A Nigel Brooks, Gregory R Carr, Glenn Hatter, Barry R Hayter, Kathryn J Hill, Nicholas J Howe, Rhys D O Jones, David Jude, Scott G Lamont, Sarah A Loddick, Heather L McFarland, Zaieda Parveen, Alfred A Rabow, Gorkhn Sharma-Singh, Natalie C Stratton, Andrew G Thomason, Dawn Trueman, Graeme E Walker, Stuart L Wells, Joanne Wilson, J Matthew Wood

2162 related Products with: Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer.

5mg100ug1 ml100.00 ug100ug100ug

Related Pathways