BAG-1: A novel strategy for targeting the androgen receptor splice variants in castrate resistant prostate cancer.

Lead Research Organisation: Institute of Cancer Research
Department Name: Division of Cancer Therapeutics

Abstract

Scientific/medical context of research?
Prostate cancer is the commonest male cancer (41,000 diagnosed in 2010) and the second commonest (10,700 died in 2010) cause of male cancer death in the UK. One man dies of prostate cancer every hour in the UK. The growth of the prostate is dependent on hormones (androgens). Hormones are the body's chemical messengers that stimulate cell growth through binding their receptors (androgen receptor). Prostate cancer develops when prostate cells grow uncontrollably. This is initially dependent on androgens. If diagnosed early prostate cancer can be cured by surgery and/or radiotherapy. However, 30% of cases will relapse and more than 20% of cases will present with widespread (metastatic) disease that is incurable. Initial treatment strategies to lower androgen levels provide robust responses in 90% of cases (hormone naive prostate cancer). Unfortunately, in time, nearly all cases progress to fatal disease that no longer responds to such therapies (castrate resistant prostate cancer). One mechanism driving castrate resistance is the identification of structurally altered androgen receptors (splice variants). These are permanently active and do not bind androgens rendering current therapies ineffective. There are currently no clinically available treatment strategies that target the androgen receptor splice variants and this is a critical area of unmet research and clinical need. BAG-1 is a protein found at increased levels in castrate resistant prostate cancer compared to hormone naive prostate cancer. BAG-1 activates both the androgen receptor and androgen receptor splice variants in prostate cancer. Techniques lowering BAG-1 protein levels inhibit the growth of prostate cancer cells. BAG-1 provides a novel therapeutic target to inhibit the androgen receptor splice variants and impact on the survival of patients with castrate resistant prostate cancer.

What is the research trying to achieve?
This fellowship will determine BAG-1 protein levels in patient biopsies and correlate this with patient survival and treatment responses to identify BAG-1 as a prognostic biomarker (predictor of survival and treatment response) in castrate resistant prostate cancer. It will identify BAG-1 as a critical regulator of androgen receptor and androgen receptor splice variant signalling driving castrate resistance and therapeutic resistance in prostate cancer. The fellowship will identify BAG-1 as a novel therapeutic target for anticancer drug discovery efforts in castrate resistant prostate cancer.

Why is this important?
There are no clinically available therapies that target androgen receptor splice variants in castrate resistant prostate cancer. Targeting BAG-1 provides a strategy to overcome castrate resistance and therapeutic resistance improving patient survival in this common disease.

Who is carrying out the research?
Dr Adam Sharp is a specialist registrar in medical oncology at the Royal Marsden Hospital in London. He completed his Bachelor of Science (Biochemistry and Pharmacology) and Doctor of Philosophy (Cancer Sciences) before undertaking his medical training. His career ambition is to be an academic medical oncologist with a laboratory focused on translational research within the field of cancer therapeutics. This fellowship will be carried out under the supervision of Professors Johann de Bono and Paul Workman who are key opinion leaders within the fields of drug discovery, drug development, chaperone proteins and prostate cancer medicine. Dr Sharp will be based in the Cancer Therapeutics Unit at the Institute of Cancer Research, the top rated academic drug discovery unit worldwide. The fellowship will initiate a consortium (sponsors and collaborators) of international leaders within the fields of BAG-1, androgen receptor, chaperone proteins, drug discovery and prostate cancer medicine to ensure the greatest scientific and clinical impact of this fellowship.

Technical Summary

Aims/Objectives:
BAG-1, Androgen Receptor (AR), AR spliced variant-7 (ARV7) and Ki67 mRNA and protein expression will be correlated with survival from castrate resistant prostate cancer (CRPC). The BAG-1L:AR/ARV7 interaction and BAG-1 regulation of AR/ARV7 signalling will be determined in prostate cancer (PC) cell lines. The role of BAG-1 in driving castration and treatment resistance in PC will be investigated. The ability of small molecules to reverse BAG-1 function in PC will be determined and assays will be established for drug discovery screening efforts.

Methodology:
NanoString technology will be used to determine mRNA levels in PC patient biopsies. We have generated novel monoclonal antibodies to ARV7 for use in immunohistochemistry (IHC) and immunofluorescence (IF) . Protein expression will be determined in PC patient biopsies using IHC and IF. Co-immunoprecipitation experiments will characterise the interaction between BAG-1L and AR/ARV7 in PC cell lines (PC3, LNCaP, VCaP and 22RV1). BAG-1L regulation of AR target genes (luciferase reporter assays, reverse transcription polymerase chain reaction and RNA-seq) will be determined. Clonogenic assays will determine the role of BAG-1 in both castration and therapeutic resistance.

Scientific opportunities:
Establish multispectral imaging and NanoString technology for the use in tissue biopsies from PC patient tumour samples. The fellowship will provide new knowledge into regulation of nuclear hormone receptors providing new experimental tools to explore key physiological and pathological pathways and opportunities for drug discovery efforts targeting ARsv.

Medical opportunities:
Develop predictive and prognostic biomarkers for the management of CRPC and identify novel therapeutic strategies for treating CRPC.

Career opportunities:
Pre-clinical drug discovery under international leaders at the world's top rated academic drug discovery unit and highly active and effective drug development unit

Planned Impact

Who will benefit and how will they benefit from the research?

Dr Adam Sharp (the Fellow):
The fellowship will provide me with world class postdoctoral training under the supervision of key opinion leaders in their respective fields at the top rated academic drug discovery unit. This training will allow me to build on my promising academic career and progress to a senior clinician scientist position. In addition, it will provide experience of clinical drug development in a highly active and effective drug development unit. This will support my progress towards my career ambition of becoming a leading British academic medical oncologist with a laboratory focused on translational research within cancer therapeutics. Throughout this time I will make contributions to drug discovery and development providing ongoing benefit to cancer patients.

Prof Myles Brown, Prof Andrew Cato, Prof Graham Packham and Mr Ramsey Cutress (the collaborators):
My collaborators are key opinion leaders in the research fields of BAG-1, androgen receptor and prostate cancer. The collaborations will provide direct access to the data produced and free transfer of validated laboratory reagents between groups. The initiation of such a consortium will ensure focus within each group to avoid duplication and competition. This will ensure rapid progress of the project and greatest impact within the prostate cancer research community. These collaborations will form part of further applications to pursue drug discovery in this research field.

Wider research community:
Regulation of the nuclear hormone receptors (NHR) implications beyond prostate cancer. New knowledge on these pathways is important for other cancer types (oestrogen receptor and breast cancer). In addition, NHR signalling is important in regulating other physiological and pathological pathways (reproduction, development, metabolism, diabetes and obesity). Therefore BAG-1 may have important roles in other disease processes. This provides impact beyond my immediate research environment and could further impact a variety of conditions affecting world health.

Prostate cancer patients and their families:
The fellowship and associated activities will impact upon prostate cancer patients and their families. The fellowship will aim to identify a group of patients that do not respond to conventional cytotoxics and endocrine therapies. This will impact on patients' quality of life by sparing toxicities associated with treatments that are ineffective. More critically, it will identify therapeutic targets that improve the survival of this cohort of patients. Patients and their families will have the opportunity to attended the institute of cancer research open day and discuss my research. This will give them the chance to provide their own views on my research going forward.

A-level students:
To engage the local community I will deliver workshops within local schools to stimulate the bright minds of the future. These workshops will be aimed at A-level science students to discuss potential career opportunities in medicine and science using examples from my career path.

In the short term the fellowship will broaden knowledge on regulation of NHR pathway that can be applied to prostate cancer and other pathologies. It will provide A-level students with inspiration to follow careers in medicine and science. In the long-term it will lead to new therapies for cancers and other disease impacting on the nations health. In addition, identifying prostate cancers that don't respond to conventional treatments may change treatment algorithms and health service policies. Finally, I will gain both research (pre-clinical drug discovery) and clinical (drug development unit) skills that will allow me to achieve my career ambition and make ongoing contributions to anticancer drug discovery in the United Kingdom.

Publications

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Boysen G (2018) SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Lambros MB (2018) Single-Cell Analyses of Prostate Cancer Liquid Biopsies Acquired by Apheresis. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Nava Rodrigues D (2019) RB1 Heterogeneity in Advanced Metastatic Castration-Resistant Prostate Cancer. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Paschalis A (2018) Alternative splicing in prostate cancer. in Nature reviews. Clinical oncology

 
Description Challenge Award (Co-I and Young Investigator)
Amount $2,000,000 (USD)
Organisation Prostate Cancer Foundation 
Sector Charity/Non Profit
Country Global
Start 09/2016 
End 09/2018
 
Description Department of Defence Award (Co-I)
Amount $1,000,000 (USD)
Organisation Department of Defense 
Sector Public
Country United States
Start 01/2017 
End 01/2020
 
Description Identifying and validating actionable targets to block androgen receptor signalling (Co-Investigator)
Amount £500,000 (GBP)
Funding ID N/A 
Organisation Prostate Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
End 09/2021
 
Description Medical Research Foundation: Conference travel award (PI)
Amount £1,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2015 
End 03/2019
 
Description Prostate Cancer Foundation Young Investigator Award
Amount $225,000 (USD)
Funding ID NA 
Organisation Prostate Cancer Foundation 
Sector Charity/Non Profit
Country Global
Start 10/2018 
End 10/2021
 
Description Targeting BAG-1L: A novel therapeutic strategy to overcome aberrant androgen receptor signalling in castration resistant prostate cancer
Amount £60,000 (GBP)
Funding ID MR/M018318/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 09/2018
 
Description Targeting CBP/p300 to Suppress Oncogenic Transcription Factors in Advanced Prostate Cancer
Amount $1,000,000 (USD)
Organisation Prostate Cancer Foundation 
Sector Charity/Non Profit
Country Global
Start 12/2017 
End 12/2019
 
Description Transforming lethal prostate cancer care through disease molecular sub-classification and predictive biomarker analytic validation and clinical outcome (Co-investigator)
Amount £1,200,000 (GBP)
Organisation Prostate Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2017 
End 10/2020
 
Description Andy Cato (Karlsruhe Institute of Technology, Germany) and Myles Brown (Dana Faber, USA) 
Organisation Dana-Farber Cancer Institute
Country United States 
Sector Hospitals 
PI Contribution Currently writing a manuscript on the role of co-regulators of the androgen receptor in prostate caner in which with have analysed protein expression in a cohort of prostate cancer patients.
Collaborator Contribution This has supported the Cato and Bron labs ongoing work on the functional analysis of co-regulators in the function of the androgen receptor. The collaboration has also enabled me to gain an MRC clinical research training fellowship.
Impact Medical Research Council Clinical Research Training Fellowship
Start Year 2015
 
Description Andy Cato (Karlsruhe Institute of Technology, Germany) and Myles Brown (Dana Faber, USA) 
Organisation Karlsruhe Institute of Technology
Country Germany 
Sector Academic/University 
PI Contribution Currently writing a manuscript on the role of co-regulators of the androgen receptor in prostate caner in which with have analysed protein expression in a cohort of prostate cancer patients.
Collaborator Contribution This has supported the Cato and Bron labs ongoing work on the functional analysis of co-regulators in the function of the androgen receptor. The collaboration has also enabled me to gain an MRC clinical research training fellowship.
Impact Medical Research Council Clinical Research Training Fellowship
Start Year 2015
 
Description David Waugh (University of Belfast) and Andrea Alimonti (Bellinzona; IOR). 
Organisation Queen's University Belfast
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration on targeting Myeloid-derived suppressor cells in advanced prostate cancer; allowed the initiation of a clinical trial to develop such agents in advanced prostate cancer
Collaborator Contribution Cell biology as translational component of a clinical trial.
Impact Initiation of clinical trail to commence in mid-late 2016.
Start Year 2016
 
Description Jun Luo (John Hopkins University) and Stephen Plymate (Washington University) 
Organisation Johns Hopkins University
Country United States 
Sector Academic/University 
PI Contribution Development of novel analytical assays to determine AR-V7 expression in prostate cancer; in addition to developing novel therapeutics against AR-V7 to treat advanced prostate cancer
Collaborator Contribution Assay development
Impact One manuscript and two poster presentations (listed in portfolio)
Start Year 2016
 
Description Karen Knudsen 
Organisation Thomas Jefferson University
Country United States 
Sector Academic/University 
PI Contribution Pre-clinical interrogation of CBP/p300 inhibitors in advanced prostate cancer.
Collaborator Contribution As above
Impact PCF Challenge Award (see grants)
Start Year 2017
 
Description Myles Brown 
Organisation Dana Farber Harvard Cancer Center
PI Contribution Pre-clinical evaluation of CBP/p300 in advanced prostate cancer and development of novel therapeutics for advanced prostate cancer
Collaborator Contribution As above
Impact PCF challenge award in 2016 and 2017; in addition to my own MRC fellowship.
Start Year 2016
 
Description Ram Mani (University of SouthWestern; USA) and Ganesh Raj (University of South Western) 
Organisation University of Texas Southwestern Medical Center
Country United States 
Sector Academic/University 
PI Contribution To investigate the role of BRD4 in advanced prostate cancer; with particular focus on treatment (Drug and radiation) resistance. Clinical samples/cohorts to support biological rationale and pre-clinical biology.
Collaborator Contribution Pre-clinical biology to support our clinical/translational work.
Impact Manuscript in preparation and grant funding
Start Year 2016
 
Description Stephen Plymate (Washington, USA), Andy Cato (Karlsruhe Institute of Technology, Germany) and Myles Brown (Dana Faber, USA) 
Organisation Dana-Farber Cancer Institute
Country United States 
Sector Hospitals 
PI Contribution Prostate caner foundation challenge award in which I am a young investigator awarded 2 million USD between four collaborators to investigate the role of BAG-1L as a novel therapeutic target to inhibit androgen receptor function in advanced prostate cancer
Collaborator Contribution Cell biology and technological expertise
Impact Manuscript under review, oral presentation AACR 2016, poster presentation (three occasions), ongoing funding.
Start Year 2016
 
Description Stephen Plymate (Washington, USA), Andy Cato (Karlsruhe Institute of Technology, Germany) and Myles Brown (Dana Faber, USA) 
Organisation Karlsruhe Institute of Technology
Country Germany 
Sector Academic/University 
PI Contribution Prostate caner foundation challenge award in which I am a young investigator awarded 2 million USD between four collaborators to investigate the role of BAG-1L as a novel therapeutic target to inhibit androgen receptor function in advanced prostate cancer
Collaborator Contribution Cell biology and technological expertise
Impact Manuscript under review, oral presentation AACR 2016, poster presentation (three occasions), ongoing funding.
Start Year 2016
 
Description Stephen Plymate (Washington, USA), Andy Cato (Karlsruhe Institute of Technology, Germany) and Myles Brown (Dana Faber, USA) 
Organisation University of Washington
Country United States 
Sector Academic/University 
PI Contribution Prostate caner foundation challenge award in which I am a young investigator awarded 2 million USD between four collaborators to investigate the role of BAG-1L as a novel therapeutic target to inhibit androgen receptor function in advanced prostate cancer
Collaborator Contribution Cell biology and technological expertise
Impact Manuscript under review, oral presentation AACR 2016, poster presentation (three occasions), ongoing funding.
Start Year 2016
 
Description Yan Dong (Tulane Cancer Center), Stephen Plymate (Washington University), Julian Blagg (Institute of Cancer Research) and Bissan Al-lazikani (Institute of Cancer Research) 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution Succesful application for Academic Clinical Lecturer starter grant to study androgen receptor N-terminal interacting co-regulators.
Collaborator Contribution Mentorship, lab reagents and ongoing advice.
Impact Academic Clinical Lecturer starter grant
Start Year 2015
 
Description Yan Dong (Tulane Cancer Center), Stephen Plymate (Washington University), Julian Blagg (Institute of Cancer Research) and Bissan Al-lazikani (Institute of Cancer Research) 
Organisation Tulane University
Country United States 
Sector Academic/University 
PI Contribution Succesful application for Academic Clinical Lecturer starter grant to study androgen receptor N-terminal interacting co-regulators.
Collaborator Contribution Mentorship, lab reagents and ongoing advice.
Impact Academic Clinical Lecturer starter grant
Start Year 2015
 
Description Yan Dong (Tulane Cancer Center), Stephen Plymate (Washington University), Julian Blagg (Institute of Cancer Research) and Bissan Al-lazikani (Institute of Cancer Research) 
Organisation University of Washington
Country United States 
Sector Academic/University 
PI Contribution Succesful application for Academic Clinical Lecturer starter grant to study androgen receptor N-terminal interacting co-regulators.
Collaborator Contribution Mentorship, lab reagents and ongoing advice.
Impact Academic Clinical Lecturer starter grant
Start Year 2015
 
Description 6th Form School Visit (Burgess Hill School for Girls) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Talk on cancer biology and drug discovery to 6th form college students interested in a career in science and/or medicine.
Year(s) Of Engagement Activity 2018
 
Description 6th Form School Visit (Francis Holland School) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Talk on cancer biology and drug discovery to 6th form college students interested in a career in science and/or medicine.
Year(s) Of Engagement Activity 2018
 
Description 6th Form School Visit (Wilson's School) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Talk on cancer biology and drug discovery to 6th form college students interested in a career in science and/or medicine.
Year(s) Of Engagement Activity 2018
 
Description 6th Form Visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk to 6th form on opportunities in science and medicine.
Year(s) Of Engagement Activity 2017
 
Description 6th form school visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I pride myself on engagement events with the local schools and enthusing bright minds of the future. I therefore set up an annual visit to a local school whereby I give a presentation on our drug development work and discuss how they would approach such challenges.
Year(s) Of Engagement Activity 2016
 
Description Biomedical Research Centre (Royal Marsden Hospital and Institute of Cancer Research) trainees forum 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact 20 to 30 healthcare professionals looking for career development advice. Sat on expert panel to explain route to current position and answer questions on my career.
Year(s) Of Engagement Activity 2015
 
Description Central Europe Middle East and Asia (CEMA) Pink Day 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Visited BBC to discuss drug discovery and development.
Year(s) Of Engagement Activity 2017
 
Description Fellowship applications: An introduction 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Discussion about winning fellowships and applications process with potential applicants to explain my experience.
Year(s) Of Engagement Activity 2016
 
Description Institute of Cancer Research Schools Open Evening 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact More than 100 students from local schools attended the Institute of Cancer Research for the evening to learn about our work. I was involved in the stall explaining the transition of cancer treatments from the laboratory to the patient.
Year(s) Of Engagement Activity 2015
 
Description Pre School Visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Visited Pre School and gave a presentation on "What do doctors do?"
Year(s) Of Engagement Activity 2018
 
Description Prostate Cancer UK Legacy Event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I gave a presentation on work supported by prostate caner UK and focused on the importance of fellowships that allow young researchers to forge a career in science.
Year(s) Of Engagement Activity 2016
 
Description Prostate Cancer UK Pioneers Evening 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Panel debate in London that I was a member of to discuss keeping bright minds in science; organised by prostate cancer UK.
Year(s) Of Engagement Activity 2016
 
Description Royal Marsden Drug Development Patient Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Drug development Open Day in which I discussed research with patient and their relatives.
Year(s) Of Engagement Activity 2016
 
Description Widening Participation Visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Schools visited our institute and I engaged with them to discuss our work including drug discovery and development.
Year(s) Of Engagement Activity 2017