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.
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
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.
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.
Organisations
- Institute of Cancer Research (Fellow, Lead Research Organisation)
- Vancouver Prostate Centre (Collaboration)
- Dana-Farber Cancer Institute (Collaboration)
- Thomas Jefferson University (Collaboration)
- Newcastle University (Collaboration)
- QUEEN'S UNIVERSITY BELFAST (Collaboration)
- UNIVERSITY OF OXFORD (Collaboration)
- Karlsruhe Institute of Technology (Collaboration)
- Beth Israel Deaconess Hospital (Collaboration)
- Institute of Cancer Research UK (Collaboration)
- Johns Hopkins University (Collaboration)
- Dana Farber Harvard Cancer Center (Collaboration)
- Tulane University (Collaboration)
- Fred Hutchinson Cancer Research Center (FHCRC) (Collaboration)
- University of Texas Southwestern Medical Center (Collaboration)
- University of Washington (Collaboration)
People |
ORCID iD |
| Adam Sharp (Principal Investigator / Fellow) |
Publications
Zafeiriou Z
(2019)
Genomic Analysis of Three Metastatic Prostate Cancer Patients with Exceptional Responses to Carboplatin Indicating Different Types of DNA Repair Deficiency.
in European urology
Welti J
(2018)
Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC).
in Clinical cancer research : an official journal of the American Association for Cancer Research
Welti J
(2021)
Targeting the p300/CBP Axis in Lethal Prostate Cancer.
in Cancer discovery
Sowalsky AG
(2021)
AR-V7 biomarker testing for primary prostate cancer: The ongoing challenge of analytical validation and clinical qualification.
in Cancer treatment and research communications
Sowalsky AG
(2022)
Re: Heng Li, Yucong Zhang, Dong Li, et al. Androgen Receptor Splice Variant 7 Predicts Shorter Response in Patients with Metastatic Hormone-sensitive Prostate Cancer Receiving Androgen Deprivation Therapy. Eur Urol 2021;79:879-86 AR-V7 is Rare in Hormone-sensitive Prostate Cancer: AR-V7 is Rare in Hormone-sensitive Prostate Cancer.
in European urology
Sowalsky AG
(2022)
Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer.
in Clinical cancer research : an official journal of the American Association for Cancer Research
Sharp A
(2019)
Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer.
in The Journal of clinical investigation
Sharp A
(2016)
Targeting Androgen Receptor Aberrations in Castration-Resistant Prostate Cancer.
in Clinical cancer research : an official journal of the American Association for Cancer Research
| Description | 219594/Z/19/Z, 'Elucidating and Treating Chromosome 1q (MCL-1) Amplified Prostate Cancer |
| Amount | £1,200,000 (GBP) |
| Funding ID | 219594/Z/19/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2020 |
| End | 09/2025 |
| 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 | Public |
| 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 | Public |
| 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 | Ian Mills |
| Organisation | University of Oxford |
| Department | Nuffield Department of Surgical Sciences Oxford |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Transfer of reagents (both ways) to support research; cell lines and next generation sequencing/transcriptomic data associated with patient derived xenografts and patients. |
| Collaborator Contribution | Transfer of reagents (both ways) to support research; modified cell lines to support our research. |
| Impact | None yet |
| Start Year | 2019 |
| Description | Jennifer Munkley |
| Organisation | Newcastle University |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Collaboration on detecting metabolites in the urine of prostate cancer patients; have provided 50 urine samples from patients with metastatic castration resistant (lethal) prostate cancer. |
| Collaborator Contribution | Analysis of the samples |
| Impact | Non applicable |
| Start Year | 2019 |
| 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 |
| Country | United States |
| Sector | Hospitals |
| 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 | Nathan Lack |
| Organisation | Vancouver Prostate Centre |
| Country | Canada |
| Sector | Hospitals |
| PI Contribution | Awarded Academy of Medical Sciences Collaborative grant to build collaboration between Sharp and Lack Lab to build preliminary data to support follow on grant funding investigating strategies to overcome endocrine resistance in lethal prostate cancer. |
| Collaborator Contribution | Awarded Academy of Medical Sciences Collaborative grant to build collaboration between Sharp and Lack Lab to build preliminary data to support follow on grant funding investigating strategies to overcome endocrine resistance in lethal prostate cancer. |
| Impact | Grant under review |
| Start Year | 2021 |
| Description | Peter Nelson |
| Organisation | Fred Hutchinson Cancer Research Center (FHCRC) |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Collaboration on recently successful Clinican Scientist Application; we will interrogate novel ways to treat lethal prostate caner focused on using patient derived models. |
| Collaborator Contribution | Patient samples and patient derived models. |
| Impact | J Clin Invest. 2019 Jan 2;129(1):192-208. doi: 10.1172/JCI122819. Epub 2018 Nov 26. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. Sharp A1,2, Coleman I3, Yuan W1, Sprenger C4, Dolling D1, Rodrigues DN1, Russo JW5, Figueiredo I1, Bertan C1, Seed G1, Riisnaes R1, Uo T4, Neeb A1, Welti J1, Morrissey C4, Carreira S1, Luo J6, Nelson PS3,4, Balk SP5, True LD4, de Bono JS1,2, Plymate SR4,7. |
| Start Year | 2019 |
| 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 Balk |
| Organisation | Beth Israel Deaconess Hospital |
| Country | United States |
| Sector | Hospitals |
| PI Contribution | Collaboration with Prof. Balk on my recent successful application for a Clinician Scientist Application to the Wellcome Trust; we will work together to develop strategies that target anti-apoptotic proteins in lethal prostate cancer. |
| Collaborator Contribution | Advice, reagents and models to support fast progression of my research program. |
| Impact | J Clin Invest. 2019 Jan 2;129(1):192-208. doi: 10.1172/JCI122819. Epub 2018 Nov 26. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. Sharp A1,2, Coleman I3, Yuan W1, Sprenger C4, Dolling D1, Rodrigues DN1, Russo JW5, Figueiredo I1, Bertan C1, Seed G1, Riisnaes R1, Uo T4, Neeb A1, Welti J1, Morrissey C4, Carreira S1, Luo J6, Nelson PS3,4, Balk SP5, True LD4, de Bono JS1,2, Plymate SR4,7. |
| Start Year | 2019 |
| 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 College (Wilson's School) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | A talk on careers in medicine and science to the preparation for medical school applications program at Wilsons School. |
| Year(s) Of Engagement Activity | 2019 |
| 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 | A career in medicine - questions and answers |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | A question and answers session with students from Wilson's School with regard medicine and research; and career advise and progression through an academic carrier as a physician. |
| Year(s) Of Engagement Activity | 2020 |
| 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 | Clinician scientists and precision medicine |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Talk to preparation for medicine course at Wilson's School which is local to the Institute of Cancer Research; follow up question and answers session with regard career opportunities and academic pathways in medicine. |
| Year(s) Of Engagement Activity | 2020 |
| 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 Legacy Event (Southampton) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Talk on my career and the work that I do to supporters of Prostate Cancer UK. |
| Year(s) Of Engagement Activity | 2019 |
| 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 |