Characterisation of a novel series of small molecule androgen receptor modulators in prostate cancer

Lead Research Organisation: Newcastle University
Department Name: Northern Institute for Cancer Research

Abstract

Prostate cancer causes approximately 10,000 deaths in the UK each year. Current treatments attempt to prevent the action of the androgen receptor, a protein that drives prostate cancer growth. Unfortunately, these treatments are not effective in the long-term and the generation of disease that no longer responds to this therapy, termed hormone-refractory prostate cancer (HRPC), is common and often fatal. Therefore, the key goal for researchers is to develop new drugs that can be used to treat this disease.

The androgen receptor remains an important driving force in the development of HRPC and therefore the generation of new agents that can permanently block it?s function are necessary to effectively treat the disease.

This project will study the effect of a new panel of drugs that can inactivate the androgen receptor in several model systems of HRPC. These studies will provide important information regarding the effect of these agents on androgen receptor action and growth of prostate cancer cells. Ultimately, this work will be important for determining the effectiveness of these drugs as future therapies for prostate cancer treatment.

Technical Summary

Prostate cancer (CaP) causes approximately 10,000 deaths per year in the UK alone. Current treatments for the disease attempt to inactivate the androgen receptor (AR), a member of the nuclear hormone receptor family of transcription factors, that regulates genes involved in prostate growth and transformation. Initial response to androgen-ablation therapy is good, but in most cases, the cancer recurs in a more aggressive form that is no longer responsive to hormonal therapy and is termed hormone-refractory prostate cancer (HRPC). There is a requirement therefore to develop new treatments that are effective against HRPC.

The fact that the AR is expressed and functional in HRPC, and is important for tumour expansion, indicates that the receptor remains a prominent target for therapy. Therefore, attenuating the function of the AR via distinct, non-conventional mechanisms in HRPC by novel receptor modulators is one avenue of research that requires attention.

AstraZeneca have identified a series of novel compounds that reduce AR activity in vivo as demonstrated by attenuation of testosterone stimulated growth of sexual accessory organs in both immature weanling rats and in mature castrated rats. Importantly, preliminary studies in vitro and in vivo indicate that the mechanism of repression is distinct from currently used adjuvant therapies and may lead to efficacy in HRPC. Further characterisation of these compounds is therefore vital for translation into the clinical setting.

To this end, we plan to perform the following experiments:

i. The effect of these novel AR modulators on transcriptional activity and cellular movement of the receptor will be assessed using a panel of CaP cell line models that mimic androgen-dependent and HRPC disease. We will also assess receptor turnover in response to compound treatment and identify enzymes responsible for driving modulator activity.

ii. The efficacy of the novel agents will be assessed in vivo using either subcutaneous xenograft or hollow fibre models of HRPC, incorporating androgen-insensitive cell lines. Tumour growth and proliferation will be determined and ex vivo analysis of disease markers will be performed by immunohistochemistry.

Ultimately, this study will characterise the efficacy of these novel AR modulators in both in vitro and in vivo models that will be a major step towards the generation of a new and much needed treatment for HRPC.
 
Description NCRI Biomarkers and Imaging Group
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description CRUK Newcastle Cancer Centre - Astra Zeneca
Amount £130,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2010 
End 09/2014
 
Description MICA
Amount £313,973 (GBP)
Funding ID BH161736 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 01/2020
 
Description PCC Project grant
Amount £198,000 (GBP)
Organisation Prostate Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Research Interaction
Amount £57,706 (GBP)
Funding ID BH164904 
Organisation CellCentric Ltd 
Sector Private
Country United Kingdom
Start 02/2017 
End 09/2018
 
Description Sir William Edmond Harker Foundation
Amount £120,000 (GBP)
Organisation Newcastle University 
Department Dr William Edmund Harker Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 08/2011 
End 12/2015
 
Title AR mutants 
Description Generated mutant derivatives of Androgen Receptor plasmids 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Useful reagents for target validation 
 
Title Assay development 
Description Novel assays developed for research project 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2009 
Provided To Others? Yes  
Impact Efficient assay development. Reproducible, reliable and high throughput assay at lower cost than previously developed 
 
Title Clinical trial of prostate cancer drug 
Description Drug developed by Astra Zeneca partner. Detailed characterisation of lead drug and derived drugs led to selection of drug for clinical trials in prostate cancer 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact Potential use as a drug for treatment of advanced prostate cancer 
 
Title LNCaP Variants 
Description Anti-androgen resistant LNCaP variants 
Type Of Material Cell line 
Provided To Others? No  
Impact Useful for in vivo model studies 
 
Title Standardised platforms 
Description Integration of AZ and Newcastle research platforms 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact Speeded up research development, integration across 2 collaborating sites 
 
Description AZ link 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Supply of reagents and expert advise and planning of a series of experiments
Collaborator Contribution Collaborator visits and access to resources at partner sites and exchange of materials
Impact Newly funded PhD studentship
Start Year 2009
 
Description Astex Collaboration 
Organisation Astex Pharmaceuticals
Department Astex Therapeutics Ltd
Country United Kingdom 
Sector Private 
PI Contribution Reagents, established expertise
Collaborator Contribution Access to fragment based design of small molecule inhibitors. Structural Biology.
Impact Preliminary data on screening for inhibitors of androgen receptor inhibitors in prostate cancer
Start Year 2011
 
Description Tokai - anti-androgen therapy 
Organisation Tokai Pharmaceuticals Inc
Country United States 
Sector Private 
PI Contribution Identified a deubiquitinase enzyme that is targetted by small molecule anti-androgen produced by Tokai
Collaborator Contribution Provide small molecules for study in collaboration
Impact Funded research in our laboratories to explore Tokai small molecules and to develop more potent small molecules that are beneficial in prostate cancer therapy
Start Year 2015
 
Title Inhibitors of androgen receptor in prostate cancer 
Description Novel inhibitors of androgen receptor function in prostate cancer 
IP Reference Insufficient Information 
Protection Patent granted
Year Protection Granted
Licensed No
Impact Potential for use in advanced prostate cancer treatment
 
Title AZ inhibitors of AR 
Description Drug for potential use in treatment of advanced prostate cancer 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2011
Development Status On hold
Clinical Trial? Yes
Impact New therapeutic drug to be included in the treatment of advanced prostate cancer 
URL https://clinicaltrials.gov/show/NCT01162395
 
Description Cancer fund raising event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Short talk on research highlights to date

Positive interaction with patient groups and stimulated their further interest to lobby government , MPs and specific prostate charities to devote more monies to this research area
Year(s) Of Engagement Activity 2008,2009,2010
 
Description Charity Fun Run 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Short presentation of research to large audience (primarily female) of between 3000-6000 audience. Including interviews with local press and local radio.

Informal discussions with smaller groups of cancer sufferers/ survivors and patient representative group
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Institute Open Days 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 3-4 hour planned session, 2-3 times yearly, on a Saturday morning. Visits of approx 100 members of public. Short presentations and demonstrations of equipment by 4-6 research groups. Closing with 1 to 1 discussions over coffee/tea.

Contact maintained with several individual members of public
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Movember Fundraising - Prostate Cancer Awareness 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Approx 100 workers from Proctor and Gamble PLC made aware of prostate cancer (briefly mentioned other cancers) risk factors and nature of research programme to combat disease

2012 gave two talks to different groups and this stimulated a series of talks for 2013 and additional events related to fundraising and public awareness of prostate cancer
Year(s) Of Engagement Activity 2012,2013
URL http://www.uk.pg.com http://uk.movember.com/
 
Description Outreach High School Interaction 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Series of workshops with Science School Teachers (5-20 participants)

Introduction of current science research and update on current research technologies
Year(s) Of Engagement Activity 2010,2011
 
Description Robson 24 hr Run 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Robson provided 15 minute presentation of NICR research and held 1 to 1 discussions with cancer sufferers/survivors and their friend and families.

Increased fundraising potential and provided accurate information for public interested in cancer research
Year(s) Of Engagement Activity 2008,2009,2010
 
Description School visit - Gaughan 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Gaughan as RC UK Fellow had meetings with local teachers to discuss workshops for school students. Presentations from Gaughan to teachers. Outreach being extended to presentations to school children.

Continuing programme to encourage students from underachieving schools to engage with science
Year(s) Of Engagement Activity 2008,2009,2010
 
Description Shaheen Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Open Day presentations. Series of laboratory tours and demonstrations to interested public

Accurate communication of our research
Year(s) Of Engagement Activity 2007,2008,2009,2010
 
Description Various Fundraising evenings 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Mostly evening, some weekend events where local fundraisers contributions are acknowledged. Generally short presentation made and sometimes receive cheque. Local press often in attendance for interview and photograph

Raise importance of cancer research
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010