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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

10 25 50
 
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 08/2020 
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 08/2016 
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 08/2018 
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 09/2015 
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 09/2018 
End 10/2021
 
Description Royal Society of Medicine - Targeting persistent androgen receptor in lethal prostate cancer
Amount £12,000 (GBP)
Organisation Royal Society of Medicine 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2022 
End 05/2025
 
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 09/2017 
End 10/2020
 
Description Adam Sowalsky 
Organisation National Institutes of Health (NIH)
Department National Cancer Institute (NCI)
Country United States 
Sector Public 
PI Contribution Support translational research of high risk localised prostate cancer leading too publications. Ongoing collaboratopm
Collaborator Contribution Support translational research of high risk localised prostate cancer leading too publications. Ongoing collaboration.
Impact Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer. Sowalsky AG, Figueiredo I, Lis RT, Coleman I, Gurel B, Bogdan D, Yuan W, Russo JW, Bright JR, Whitlock NC, Trostel SY, Ku AT, Patel RA, True LD, Welti J, Jimenez-Vacas JM, Rodrigues DN, Riisnaes R, Neeb A, Sprenger CT, Swain A, Wilkinson S, Karzai F, Dahut WL, Balk SP, Corey E, Nelson PS, Haffner MC, Plymate SR, de Bono JS, Sharp A. Clin Cancer Res. 2022 Aug 15;28(16):3509-3525. doi: 10.1158/1078-0432.CCR-22-0851. AR-V7 biomarker testing for primary prostate cancer: The ongoing challenge of analytical validation and clinical qualification. Sowalsky AG, Sharp A, Trostel SY, de Bono JS, Plymate SR. Cancer Treat Res Commun. 2021;28:100218. doi: 10.1016/j.ctarc.2020.100218. Epub 2020 Oct 9.
Start Year 2022
 
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 Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate Cancer. Neeb A, Figueiredo I, Bogdan D, Cato L, Stober J, Jiménez-Vacas JM, Gourain V, Lee II, Seeger R, Muhle-Goll C, Gurel B, Welti J, Nava Rodrigues D, Rekowski J, Qiu X, Jiang Y, Di Micco P, Mateos B, Bielskute S, Riisnaes R, Ferreira A, Miranda S, Crespo M, Buroni L, Ning J, Carreira S, Bräse S, Jung N, Gräßle S, Swain A, Salvatella X, Plymate SR, Al-Lazikani B, Long HW, Yuan W, Brown M, Cato ACB, de Bono JS, Sharp A. Mol Cancer Ther. 2024 Jun 4;23(6):791-808. doi: 10.1158/1535-7163.MCT-23-0354. Development and Validation of a New BAG-1L-Specific Antibody to Quantify BAG-1L Protein Expression in Advanced Prostate Cancer. Neeb A, Figueiredo I, Gurel B, Nava Rodrigues D, Rekowski J, Riisnaes R, Ferreira A, Miranda S, Crespo M, Westaby D, de Los Dolores Fenor de La Maza M, Guo C, Carmichael J, Grochot R, Tunariu N, Cato ACB, Plymate SR, de Bono JS, Sharp A. Lab Invest. 2023 Nov;103(11):100245. doi: 10.1016/j.labinv.2023.100245. Epub 2023 Aug 29. Identification of an Imidazopyridine-based Compound as an Oral Selective Estrogen Receptor Degrader for Breast Cancer Therapy. Pan M, Solozobova V, Kuznik NC, Jung N, Gräßle S, Gourain V, Heneka YM, Cramer von Clausbruch CA, Fuhr O, Munuganti RSN, Maddalo D, Blattner C, Neeb A, Sharp A, Cato L, Weiss C, Jeselsohn RM, Orian-Rousseau V, Bräse S, Cato ACB. Cancer Res Commun. 2023 Jul 27;3(7):1378-1396. doi: 10.1158/2767-9764.CRC-23-0111. Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer. Cato L, Neeb A, Sharp A, Buzón V, Ficarro SB, Yang L, Muhle-Goll C, Kuznik NC, Riisnaes R, Nava Rodrigues D, Armant O, Gourain V, Adelmant G, Ntim EA, Westerling T, Dolling D, Rescigno P, Figueiredo I, Fauser F, Wu J, Rottenberg JT, Shatkina L, Ester C, Luy B, Puchta H, Troppmair J, Jung N, Bräse S, Strähle U, Marto JA, Nienhaus GU, Al-Lazikani B, Salvatella X, de Bono JS, Cato AC, Brown M. Elife. 2017 Aug 10;6:e27159. doi: 10.7554/eLife.27159.
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 Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate Cancer. Neeb A, Figueiredo I, Bogdan D, Cato L, Stober J, Jiménez-Vacas JM, Gourain V, Lee II, Seeger R, Muhle-Goll C, Gurel B, Welti J, Nava Rodrigues D, Rekowski J, Qiu X, Jiang Y, Di Micco P, Mateos B, Bielskute S, Riisnaes R, Ferreira A, Miranda S, Crespo M, Buroni L, Ning J, Carreira S, Bräse S, Jung N, Gräßle S, Swain A, Salvatella X, Plymate SR, Al-Lazikani B, Long HW, Yuan W, Brown M, Cato ACB, de Bono JS, Sharp A. Mol Cancer Ther. 2024 Jun 4;23(6):791-808. doi: 10.1158/1535-7163.MCT-23-0354. Development and Validation of a New BAG-1L-Specific Antibody to Quantify BAG-1L Protein Expression in Advanced Prostate Cancer. Neeb A, Figueiredo I, Gurel B, Nava Rodrigues D, Rekowski J, Riisnaes R, Ferreira A, Miranda S, Crespo M, Westaby D, de Los Dolores Fenor de La Maza M, Guo C, Carmichael J, Grochot R, Tunariu N, Cato ACB, Plymate SR, de Bono JS, Sharp A. Lab Invest. 2023 Nov;103(11):100245. doi: 10.1016/j.labinv.2023.100245. Epub 2023 Aug 29. Identification of an Imidazopyridine-based Compound as an Oral Selective Estrogen Receptor Degrader for Breast Cancer Therapy. Pan M, Solozobova V, Kuznik NC, Jung N, Gräßle S, Gourain V, Heneka YM, Cramer von Clausbruch CA, Fuhr O, Munuganti RSN, Maddalo D, Blattner C, Neeb A, Sharp A, Cato L, Weiss C, Jeselsohn RM, Orian-Rousseau V, Bräse S, Cato ACB. Cancer Res Commun. 2023 Jul 27;3(7):1378-1396. doi: 10.1158/2767-9764.CRC-23-0111. Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer. Cato L, Neeb A, Sharp A, Buzón V, Ficarro SB, Yang L, Muhle-Goll C, Kuznik NC, Riisnaes R, Nava Rodrigues D, Armant O, Gourain V, Adelmant G, Ntim EA, Westerling T, Dolling D, Rescigno P, Figueiredo I, Fauser F, Wu J, Rottenberg JT, Shatkina L, Ester C, Luy B, Puchta H, Troppmair J, Jung N, Bräse S, Strähle U, Marto JA, Nienhaus GU, Al-Lazikani B, Salvatella X, de Bono JS, Cato AC, Brown M. Elife. 2017 Aug 10;6:e27159. doi: 10.7554/eLife.27159.
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 Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance. Guo C, Sharp A, Gurel B, Crespo M, Figueiredo I, Jain S, Vogl U, Rekowski J, Rouhifard M, Gallagher L, Yuan W, Carreira S, Chandran K, Paschalis A, Colombo I, Stathis A, Bertan C, Seed G, Goodall J, Raynaud F, Ruddle R, Swales KE, Malia J, Bogdan D, Tiu C, Caldwell R, Aversa C, Ferreira A, Neeb A, Tunariu N, Westaby D, Carmichael J, Fenor de la Maza MD, Yap C, Matthews R, Badham H, Prout T, Turner A, Parmar M, Tovey H, Riisnaes R, Flohr P, Gil J, Waugh D, Decordova S, Schlag A, Calì B, Alimonti A, de Bono JS. Nature. 2023 Nov;623(7989):1053-1061. doi: 10.1038/s41586-023-06696-z. Epub 2023 Oct 16.
Start Year 2016
 
Description Ganesh Raj 
Organisation University of Texas Southwestern Medical Center
Country United States 
Sector Academic/University 
PI Contribution Collaborator on personal Prostate Cancer Foundation Young Investigator Award (2018-2021) entitled Specific Targeting of mRNA Splicing as a Therapeutic Strategy for Lethal Prostate Cancer
Collaborator Contribution Providing mentorship and access to normal, benign and early prostate cancer samples
Impact Alternative splicing in prostate cancer. Paschalis A, Sharp A, Welti JC, Neeb A, Raj GV, Luo J, Plymate SR, de Bono JS. Nat Rev Clin Oncol. 2018 Nov;15(11):663-675. doi: 10.1038/s41571-018-0085-0. Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC). Welti J, Sharp A, Yuan W, Dolling D, Nava Rodrigues D, Figueiredo I, Gil V, Neeb A, Clarke M, Seed G, Crespo M, Sumanasuriya S, Ning J, Knight E, Francis JC, Hughes A, Halsey WS, Paschalis A, Mani RS, Raj GV, Plymate SR, Carreira S, Boysen G, Chinnaiyan AM, Swain A, de Bono JS; International SU2C/PCF Prostate Cancer Dream Team. Clin Cancer Res. 2018 Jul 1;24(13):3149-3162. doi: 10.1158/1078-0432.CCR-17-3571. Epub 2018 Mar 19. The landscape of RNA polymerase II-associated chromatin interactions in prostate cancer. Ramanand SG, Chen Y, Yuan J, Daescu K, Lambros MB, Houlahan KE, Carreira S, Yuan W, Baek G, Sharp A, Paschalis A, Kanchwala M, Gao Y, Aslam A, Safdar N, Zhan X, Raj GV, Xing C, Boutros PC, de Bono J, Zhang MQ, Mani RS. J Clin Invest. 2020 Aug 3;130(8):3987-4005. doi: 10.1172/JCI134260. BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer. Li X, Baek G, Ramanand SG, Sharp A, Gao Y, Yuan W, Welti J, Rodrigues DN, Dolling D, Figueiredo I, Sumanasuriya S, Crespo M, Aslam A, Li R, Yin Y, Mukherjee B, Kanchwala M, Hughes AM, Halsey WS, Chiang CM, Xing C, Raj GV, Burma S, de Bono J, Mani RS. Cell Rep. 2018 Jan 16;22(3):796-808. doi: 10.1016/j.celrep.2017.12.078. Dissecting Prognostic From Predictive Utility: Circulating AR-V7 Biomarker Testing for Advanced Prostate Cancer. Sharp A, Porta N, Lambros MBK, Welti JC, Paschalis A, Raj GV, Plymate SP, de Bono JS. J Clin Oncol. 2019 Aug 20;37(24):2182-2184. doi: 10.1200/JCO.19.01104. Epub 2019 Jul 2.
Start Year 2018
 
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 
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 Upregulation of GALNT7 in prostate cancer modifies O-glycosylation and promotes tumour growth. Scott E, Hodgson K, Calle B, Turner H, Cheung K, Bermudez A, Marques FJG, Pye H, Yo EC, Islam K, Oo HZ, McClurg UL, Wilson L, Thomas H, Frame FM, Orozco-Moreno M, Bastian K, Arredondo HM, Roustan C, Gray MA, Kelly L, Tolson A, Mellor E, Hysenaj G, Goode EA, Garnham R, Duxfield A, Heavey S, Stopka-Farooqui U, Haider A, Freeman A, Singh S, Johnston EW, Punwani S, Knight B, McCullagh P, McGrath J, Crundwell M, Harries L, Bogdan D, Westaby D, Fowler G, Flohr P, Yuan W, Sharp A, de Bono J, Maitland NJ, Wisnovsky S, Bertozzi CR, Heer R, Guerrero RH, Daugaard M, Leivo J, Whitaker H, Pitteri S, Wang N, Elliott DJ, Schumann B, Munkley J. Oncogene. 2023 Mar;42(12):926-937. doi: 10.1038/s41388-023-02604-x. Epub 2023 Feb 1.
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 Alternative splicing in prostate cancer. Paschalis A, Sharp A, Welti JC, Neeb A, Raj GV, Luo J, Plymate SR, de Bono JS. Nat Rev Clin Oncol. 2018 Nov;15(11):663-675. doi: 10.1038/s41571-018-0085-0. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. Sharp A, Coleman I, Yuan W, Sprenger C, Dolling D, Rodrigues DN, Russo JW, Figueiredo I, Bertan C, Seed G, Riisnaes R, Uo T, Neeb A, Welti J, Morrissey C, Carreira S, Luo J, Nelson PS, Balk SP, True LD, de Bono JS, Plymate SR. J Clin Invest. 2019 Jan 2;129(1):192-208. doi: 10.1172/JCI122819. Epub 2018 Nov 26. Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer. Sharp A, Welti JC, Lambros MBK, Dolling D, Rodrigues DN, Pope L, Aversa C, Figueiredo I, Fraser J, Ahmad Z, Lu C, Rescigno P, Kolinsky M, Bertan C, Seed G, Riisnaes R, Miranda S, Crespo M, Pereira R, Ferreira A, Fowler G, Ebbs B, Flohr P, Neeb A, Bianchini D, Petremolo A, Sumanasuriya S, Paschalis A, Mateo J, Tunariu N, Yuan W, Carreira S, Plymate SR, Luo J, de Bono JS. Eur Urol. 2019 Nov;76(5):676-685. doi: 10.1016/j.eururo.2019.04.006. Epub 2019 Apr 27. Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. Zhu Y, Sharp A, Anderson CM, Silberstein JL, Taylor M, Lu C, Zhao P, De Marzo AM, Antonarakis ES, Wang M, Wu X, Luo Y, Su N, Nava Rodrigues D, Figueiredo I, Welti J, Park E, Ma XJ, Coleman I, Morrissey C, Plymate SR, Nelson PS, de Bono JS, Luo J. Eur Urol. 2018 May;73(5):727-735. doi: 10.1016/j.eururo.2017.08.009. Epub 2017 Sep 1.
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 Targeting the p300/CBP Axis in Lethal Prostate Cancer. Welti J, Sharp A, Brooks N, Yuan W, McNair C, Chand SN, Pal A, Figueiredo I, Riisnaes R, Gurel B, Rekowski J, Bogdan D, West W, Young B, Raja M, Prosser A, Lane J, Thomson S, Worthington J, Onions S, Shannon J, Paoletta S, Brown R, Smyth D, Harbottle GW, Gil VS, Miranda S, Crespo M, Ferreira A, Pereira R, Tunariu N, Carreira S, Neeb AJ, Ning J, Swain A, Taddei D; SU2C/PCF International Prostate Cancer Dream Team; Schiewer MJ, Knudsen KE, Pegg N, de Bono JS. Cancer Discov. 2021 May;11(5):1118-1137. doi: 10.1158/2159-8290.CD-20-0751. Epub 2021 Jan 11. AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer. Sardar S, McNair CM, Ravindranath L, Chand SN, Yuan W, Bogdan D, Welti J, Sharp A, Ryan NK, Knudsen LA, Schiewer MJ, DeArment EG, Janas T, Su XA, Butler LM, de Bono JS, Frese K, Brooks N, Pegg N, Knudsen KE, Shafi AA. Oncogene. 2024 Oct;43(43):3197-3213. doi: 10.1038/s41388-024-03148-4. Epub 2024 Sep 13. RB1 Heterogeneity in Advanced Metastatic Castration-Resistant Prostate Cancer. Nava Rodrigues D, Casiraghi N, Romanel A, Crespo M, Miranda S, Rescigno P, Figueiredo I, Riisnaes R, Carreira S, Sumanasuriya S, Gasperini P, Sharp A, Mateo J, Makay A, McNair C, Schiewer M, Knudsen K, Boysen G, Demichelis F, de Bono JS. Clin Cancer Res. 2019 Jan 15;25(2):687-697. doi: 10.1158/1078-0432.CCR-18-2068. Epub 2018 Sep 26.
Start Year 2017
 
Description Luke Gaughan 
Organisation Newcastle University
Country United Kingdom 
PI Contribution Supported acquisition of clinical data to support paper on androgen receptor biology in lethal prostate cancer.
Collaborator Contribution Collaboration to support efforts on androgen receptor biology in lethal prostate cancer.
Impact The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer. Adamson B, Brittain N, Walker L, Duncan R, Luzzi S, Rescigno P, Smith G, McGill S, Burchmore RJ, Willmore E, Hickson I, Robson CN, Bogdan D, Jimenez-Vacas JM, Paschalis A, Welti J, Yuan W, McCracken SR, Heer R, Sharp A, de Bono JS, Gaughan L. J Clin Invest. 2023 Nov 15;133(22):e169200. doi: 10.1172/JCI169200.
Start Year 2023
 
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 MRC Fellowship Wellcome Trust Fellowship Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate Cancer. Neeb A, Figueiredo I, Bogdan D, Cato L, Stober J, Jiménez-Vacas JM, Gourain V, Lee II, Seeger R, Muhle-Goll C, Gurel B, Welti J, Nava Rodrigues D, Rekowski J, Qiu X, Jiang Y, Di Micco P, Mateos B, Bielskute S, Riisnaes R, Ferreira A, Miranda S, Crespo M, Buroni L, Ning J, Carreira S, Bräse S, Jung N, Gräßle S, Swain A, Salvatella X, Plymate SR, Al-Lazikani B, Long HW, Yuan W, Brown M, Cato ACB, de Bono JS, Sharp A. Mol Cancer Ther. 2024 Jun 4;23(6):791-808. doi: 10.1158/1535-7163.MCT-23-0354. Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer. Cato L, Neeb A, Sharp A, Buzón V, Ficarro SB, Yang L, Muhle-Goll C, Kuznik NC, Riisnaes R, Nava Rodrigues D, Armant O, Gourain V, Adelmant G, Ntim EA, Westerling T, Dolling D, Rescigno P, Figueiredo I, Fauser F, Wu J, Rottenberg JT, Shatkina L, Ester C, Luy B, Puchta H, Troppmair J, Jung N, Bräse S, Strähle U, Marto JA, Nienhaus GU, Al-Lazikani B, Salvatella X, de Bono JS, Cato AC, Brown M. Elife. 2017 Aug 10;6:e27159. doi: 10.7554/eLife.27159.
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 Wellcome Trust Fellowship NXP800 activates the unfolded protein response, altering AR and E2F function to impact castration-resistant prostate cancer growth. Welti J, Bogdan D, Figueiredo I, Coleman I, Jiménez Vacas J, Liodaki K, Weigl F, Buroni L, Zeng W, Bernett I, Bertan C, Roumeliotis TI, Bhamra A, Rekowski J, Gurel B, Neeb AJ, Ning J, Li D, Gil VS, Riisnaes R, Miranda S, Crespo M, Ferreira A, Tunariu N, Pasqua E, Chessum N, Cheeseman M, Te Poele R, Powers M, Carreira S, Choudhary J, Clarke P, Banerji U, Swain A, Jones K, Yuan W, Workman P, Nelson PS, de Bono JS, Sharp A. Clin Cancer Res. 2025 Jan 9. doi: 10.1158/1078-0432.CCR-24-2386. Online ahead of print. BCL2 expression is enriched in advanced prostate cancer with features of lineage plasticity. Westaby D, Jiménez-Vacas JM, Figueiredo I, Rekowski J, Pettinger C, Gurel B, Lundberg A, Bogdan D, Buroni L, Neeb A, Padilha A, Taylor J, Zeng W, Das S, Hobern E, Riisnaes R, Crespo M, Miranda S, Ferreira A, Hanratty BP, Nava Rodrigues D, Bertan C, Seed G, Fenor de La Maza MLD, Guo C, Carmichael J, Grochot R, Chandran K, Stavridi A, Varkaris A, Stylianou N, Hollier BG, Tunariu N, Balk SP, Carreira S, Yuan W, Nelson PS, Corey E, Haffner M, de Bono J, Sharp A. J Clin Invest. 2024 Sep 17;134(18):e179998. doi: 10.1172/JCI179998. Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer. Sowalsky AG, Figueiredo I, Lis RT, Coleman I, Gurel B, Bogdan D, Yuan W, Russo JW, Bright JR, Whitlock NC, Trostel SY, Ku AT, Patel RA, True LD, Welti J, Jimenez-Vacas JM, Rodrigues DN, Riisnaes R, Neeb A, Sprenger CT, Swain A, Wilkinson S, Karzai F, Dahut WL, Balk SP, Corey E, Nelson PS, Haffner MC, Plymate SR, de Bono JS, Sharp A. Clin Cancer Res. 2022 Aug 15;28(16):3509-3525. doi: 10.1158/1078-0432.CCR-22-0851. Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer. Li S, Fong KW, Gritsina G, Zhang A, Zhao JC, Kim J, Sharp A, Yuan W, Aversa C, Yang XJ, Nelson PS, Feng FY, Chinnaiyan AM, de Bono JS, Morrissey C, Rettig MB, Yu J. Cancer Res. 2019 May 15;79(10):2580-2592. doi: 10.1158/0008-5472.CAN-18-2812. Epub 2019 Apr 5. Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. Zhu Y, Sharp A, Anderson CM, Silberstein JL, Taylor M, Lu C, Zhao P, De Marzo AM, Antonarakis ES, Wang M, Wu X, Luo Y, Su N, Nava Rodrigues D, Figueiredo I, Welti J, Park E, Ma XJ, Coleman I, Morrissey C, Plymate SR, Nelson PS, de Bono JS, Luo J. Eur Urol. 2018 May;73(5):727-735. doi: 10.1016/j.eururo.2017.08.009. Epub 2017 Sep 1. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. Nava Rodrigues D, Rescigno P, Liu D, Yuan W, Carreira S, Lambros MB, Seed G, Mateo J, Riisnaes R, Mullane S, Margolis C, Miao D, Miranda S, Dolling D, Clarke M, Bertan C, Crespo M, Boysen G, Ferreira A, Sharp A, Figueiredo I, Keliher D, Aldubayan S, Burke KP, Sumanasuriya S, Fontes MS, Bianchini D, Zafeiriou Z, Teixeira Mendes LS, Mouw K, Schweizer MT, Pritchard CC, Salipante S, Taplin ME, Beltran H, Rubin MA, Cieslik M, Robinson D, Heath E, Schultz N, Armenia J, Abida W, Scher H, Lord C, D'Andrea A, Sawyers CL, Chinnaiyan AM, Alimonti A, Nelson PS, Drake CG, Van Allen EM, de Bono JS. J Clin Invest. 2018 Oct 1;128(10):4441-4453. doi: 10.1172/JCI121924. Epub 2018 Sep 4.
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 Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC). Welti J, Sharp A, Yuan W, Dolling D, Nava Rodrigues D, Figueiredo I, Gil V, Neeb A, Clarke M, Seed G, Crespo M, Sumanasuriya S, Ning J, Knight E, Francis JC, Hughes A, Halsey WS, Paschalis A, Mani RS, Raj GV, Plymate SR, Carreira S, Boysen G, Chinnaiyan AM, Swain A, de Bono JS; International SU2C/PCF Prostate Cancer Dream Team. Clin Cancer Res. 2018 Jul 1;24(13):3149-3162. doi: 10.1158/1078-0432.CCR-17-3571. Epub 2018 Mar 19. The landscape of RNA polymerase II-associated chromatin interactions in prostate cancer. Ramanand SG, Chen Y, Yuan J, Daescu K, Lambros MB, Houlahan KE, Carreira S, Yuan W, Baek G, Sharp A, Paschalis A, Kanchwala M, Gao Y, Aslam A, Safdar N, Zhan X, Raj GV, Xing C, Boutros PC, de Bono J, Zhang MQ, Mani RS. J Clin Invest. 2020 Aug 3;130(8):3987-4005. doi: 10.1172/JCI134260. BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer. Li X, Baek G, Ramanand SG, Sharp A, Gao Y, Yuan W, Welti J, Rodrigues DN, Dolling D, Figueiredo I, Sumanasuriya S, Crespo M, Aslam A, Li R, Yin Y, Mukherjee B, Kanchwala M, Hughes AM, Halsey WS, Chiang CM, Xing C, Raj GV, Burma S, de Bono J, Mani RS.
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 Prostate Cancer Foundation Challenge Award Wellcome Trust Fellowship Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. Sharp A, Coleman I, Yuan W, Sprenger C, Dolling D, Rodrigues DN, Russo JW, Figueiredo I, Bertan C, Seed G, Riisnaes R, Uo T, Neeb A, Welti J, Morrissey C, Carreira S, Luo J, Nelson PS, Balk SP, True LD, de Bono JS, Plymate SR. J Clin Invest. 2019 Jan 2;129(1):192-208. doi: 10.1172/JCI122819. Epub 2018 Nov 26. BCL2 expression is enriched in advanced prostate cancer with features of lineage plasticity. Westaby D, Jiménez-Vacas JM, Figueiredo I, Rekowski J, Pettinger C, Gurel B, Lundberg A, Bogdan D, Buroni L, Neeb A, Padilha A, Taylor J, Zeng W, Das S, Hobern E, Riisnaes R, Crespo M, Miranda S, Ferreira A, Hanratty BP, Nava Rodrigues D, Bertan C, Seed G, Fenor de La Maza MLD, Guo C, Carmichael J, Grochot R, Chandran K, Stavridi A, Varkaris A, Stylianou N, Hollier BG, Tunariu N, Balk SP, Carreira S, Yuan W, Nelson PS, Corey E, Haffner M, de Bono J, Sharp A. J Clin Invest. 2024 Sep 17;134(18):e179998. doi: 10.1172/JCI179998. Targeting the Intrinsic Apoptosis Pathway: A Window of Opportunity for Prostate Cancer. Westaby D, Jimenez-Vacas JM, Padilha A, Varkaris A, Balk SP, de Bono JS, Sharp A. Cancers (Basel). 2021 Dec 23;14(1):51. doi: 10.3390/cancers14010051. Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer. Sowalsky AG, Figueiredo I, Lis RT, Coleman I, Gurel B, Bogdan D, Yuan W, Russo JW, Bright JR, Whitlock NC, Trostel SY, Ku AT, Patel RA, True LD, Welti J, Jimenez-Vacas JM, Rodrigues DN, Riisnaes R, Neeb A, Sprenger CT, Swain A, Wilkinson S, Karzai F, Dahut WL, Balk SP, Corey E, Nelson PS, Haffner MC, Plymate SR, de Bono JS, Sharp A. Clin Cancer Res. 2022 Aug 15;28(16):3509-3525. doi: 10.1158/1078-0432.CCR-22-0851.
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 Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. Sharp A, Coleman I, Yuan W, Sprenger C, Dolling D, Rodrigues DN, Russo JW, Figueiredo I, Bertan C, Seed G, Riisnaes R, Uo T, Neeb A, Welti J, Morrissey C, Carreira S, Luo J, Nelson PS, Balk SP, True LD, de Bono JS, Plymate SR. J Clin Invest. 2019 Jan 2;129(1):192-208. doi: 10.1172/JCI122819. Epub 2018 Nov 26. Alternative splicing in prostate cancer. Paschalis A, Sharp A, Welti JC, Neeb A, Raj GV, Luo J, Plymate SR, de Bono JS. Nat Rev Clin Oncol. 2018 Nov;15(11):663-675. doi: 10.1038/s41571-018-0085-0. Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate Cancer. Neeb A, Figueiredo I, Bogdan D, Cato L, Stober J, Jiménez-Vacas JM, Gourain V, Lee II, Seeger R, Muhle-Goll C, Gurel B, Welti J, Nava Rodrigues D, Rekowski J, Qiu X, Jiang Y, Di Micco P, Mateos B, Bielskute S, Riisnaes R, Ferreira A, Miranda S, Crespo M, Buroni L, Ning J, Carreira S, Bräse S, Jung N, Gräßle S, Swain A, Salvatella X, Plymate SR, Al-Lazikani B, Long HW, Yuan W, Brown M, Cato ACB, de Bono JS, Sharp A. Mol Cancer Ther. 2024 Jun 4;23(6):791-808. doi: 10.1158/1535-7163.MCT-23-0354. Development and Validation of a New BAG-1L-Specific Antibody to Quantify BAG-1L Protein Expression in Advanced Prostate Cancer. Neeb A, Figueiredo I, Gurel B, Nava Rodrigues D, Rekowski J, Riisnaes R, Ferreira A, Miranda S, Crespo M, Westaby D, de Los Dolores Fenor de La Maza M, Guo C, Carmichael J, Grochot R, Tunariu N, Cato ACB, Plymate SR, de Bono JS, Sharp A. Lab Invest. 2023 Nov;103(11):100245. doi: 10.1016/j.labinv.2023.100245. Epub 2023 Aug 29. Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC). Welti J, Sharp A, Yuan W, Dolling D, Nava Rodrigues D, Figueiredo I, Gil V, Neeb A, Clarke M, Seed G, Crespo M, Sumanasuriya S, Ning J, Knight E, Francis JC, Hughes A, Halsey WS, Paschalis A, Mani RS, Raj GV, Plymate SR, Carreira S, Boysen G, Chinnaiyan AM, Swain A, de Bono JS; International SU2C/PCF Prostate Cancer Dream Team. Clin Cancer Res. 2018 Jul 1;24(13):3149-3162. doi: 10.1158/1078-0432.CCR-17-3571. Epub 2018 Mar 19. Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer. Sowalsky AG, Figueiredo I, Lis RT, Coleman I, Gurel B, Bogdan D, Yuan W, Russo JW, Bright JR, Whitlock NC, Trostel SY, Ku AT, Patel RA, True LD, Welti J, Jimenez-Vacas JM, Rodrigues DN, Riisnaes R, Neeb A, Sprenger CT, Swain A, Wilkinson S, Karzai F, Dahut WL, Balk SP, Corey E, Nelson PS, Haffner MC, Plymate SR, de Bono JS, Sharp A. Clin Cancer Res. 2022 Aug 15;28(16):3509-3525. doi: 10.1158/1078-0432.CCR-22-0851. JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer. Paschalis A, Welti J, Neeb AJ, Yuan W, Figueiredo I, Pereira R, Ferreira A, Riisnaes R, Rodrigues DN, Jiménez-Vacas JM, Kim S, Uo T, Micco PD, Tumber A, Islam MS, Moesser MA, Abboud M, Kawamura A, Gurel B, Christova R, Gil VS, Buroni L, Crespo M, Miranda S, Lambros MB, Carreira S, Tunariu N, Alimonti A, Al-Lazikani B, Schofield CJ, Plymate SR, Sharp A, de Bono JS; , SU2C/PCF International Prostate Cancer Dream Team. Cancer Res. 2021 Feb 15;81(4):1087-1100. doi: 10.1158/0008-5472.CAN-20-1807. Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer. Sharp A, Welti JC, Lambros MBK, Dolling D, Rodrigues DN, Pope L, Aversa C, Figueiredo I, Fraser J, Ahmad Z, Lu C, Rescigno P, Kolinsky M, Bertan C, Seed G, Riisnaes R, Miranda S, Crespo M, Pereira R, Ferreira A, Fowler G, Ebbs B, Flohr P, Neeb A, Bianchini D, Petremolo A, Sumanasuriya S, Paschalis A, Mateo J, Tunariu N, Yuan W, Carreira S, Plymate SR, Luo J, de Bono JS. Eur Urol. 2019 Nov;76(5):676-685. doi: 10.1016/j.eururo.2019.04.006. Epub 2019 Apr 27.
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 Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. Sharp A, Coleman I, Yuan W, Sprenger C, Dolling D, Rodrigues DN, Russo JW, Figueiredo I, Bertan C, Seed G, Riisnaes R, Uo T, Neeb A, Welti J, Morrissey C, Carreira S, Luo J, Nelson PS, Balk SP, True LD, de Bono JS, Plymate SR. J Clin Invest. 2019 Jan 2;129(1):192-208. doi: 10.1172/JCI122819. Epub 2018 Nov 26. Alternative splicing in prostate cancer. Paschalis A, Sharp A, Welti JC, Neeb A, Raj GV, Luo J, Plymate SR, de Bono JS. Nat Rev Clin Oncol. 2018 Nov;15(11):663-675. doi: 10.1038/s41571-018-0085-0. Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate Cancer. Neeb A, Figueiredo I, Bogdan D, Cato L, Stober J, Jiménez-Vacas JM, Gourain V, Lee II, Seeger R, Muhle-Goll C, Gurel B, Welti J, Nava Rodrigues D, Rekowski J, Qiu X, Jiang Y, Di Micco P, Mateos B, Bielskute S, Riisnaes R, Ferreira A, Miranda S, Crespo M, Buroni L, Ning J, Carreira S, Bräse S, Jung N, Gräßle S, Swain A, Salvatella X, Plymate SR, Al-Lazikani B, Long HW, Yuan W, Brown M, Cato ACB, de Bono JS, Sharp A. Mol Cancer Ther. 2024 Jun 4;23(6):791-808. doi: 10.1158/1535-7163.MCT-23-0354. Development and Validation of a New BAG-1L-Specific Antibody to Quantify BAG-1L Protein Expression in Advanced Prostate Cancer. Neeb A, Figueiredo I, Gurel B, Nava Rodrigues D, Rekowski J, Riisnaes R, Ferreira A, Miranda S, Crespo M, Westaby D, de Los Dolores Fenor de La Maza M, Guo C, Carmichael J, Grochot R, Tunariu N, Cato ACB, Plymate SR, de Bono JS, Sharp A. Lab Invest. 2023 Nov;103(11):100245. doi: 10.1016/j.labinv.2023.100245. Epub 2023 Aug 29. Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC). Welti J, Sharp A, Yuan W, Dolling D, Nava Rodrigues D, Figueiredo I, Gil V, Neeb A, Clarke M, Seed G, Crespo M, Sumanasuriya S, Ning J, Knight E, Francis JC, Hughes A, Halsey WS, Paschalis A, Mani RS, Raj GV, Plymate SR, Carreira S, Boysen G, Chinnaiyan AM, Swain A, de Bono JS; International SU2C/PCF Prostate Cancer Dream Team. Clin Cancer Res. 2018 Jul 1;24(13):3149-3162. doi: 10.1158/1078-0432.CCR-17-3571. Epub 2018 Mar 19. Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer. Sowalsky AG, Figueiredo I, Lis RT, Coleman I, Gurel B, Bogdan D, Yuan W, Russo JW, Bright JR, Whitlock NC, Trostel SY, Ku AT, Patel RA, True LD, Welti J, Jimenez-Vacas JM, Rodrigues DN, Riisnaes R, Neeb A, Sprenger CT, Swain A, Wilkinson S, Karzai F, Dahut WL, Balk SP, Corey E, Nelson PS, Haffner MC, Plymate SR, de Bono JS, Sharp A. Clin Cancer Res. 2022 Aug 15;28(16):3509-3525. doi: 10.1158/1078-0432.CCR-22-0851. JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer. Paschalis A, Welti J, Neeb AJ, Yuan W, Figueiredo I, Pereira R, Ferreira A, Riisnaes R, Rodrigues DN, Jiménez-Vacas JM, Kim S, Uo T, Micco PD, Tumber A, Islam MS, Moesser MA, Abboud M, Kawamura A, Gurel B, Christova R, Gil VS, Buroni L, Crespo M, Miranda S, Lambros MB, Carreira S, Tunariu N, Alimonti A, Al-Lazikani B, Schofield CJ, Plymate SR, Sharp A, de Bono JS; , SU2C/PCF International Prostate Cancer Dream Team. Cancer Res. 2021 Feb 15;81(4):1087-1100. doi: 10.1158/0008-5472.CAN-20-1807. Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer. Sharp A, Welti JC, Lambros MBK, Dolling D, Rodrigues DN, Pope L, Aversa C, Figueiredo I, Fraser J, Ahmad Z, Lu C, Rescigno P, Kolinsky M, Bertan C, Seed G, Riisnaes R, Miranda S, Crespo M, Pereira R, Ferreira A, Fowler G, Ebbs B, Flohr P, Neeb A, Bianchini D, Petremolo A, Sumanasuriya S, Paschalis A, Mateo J, Tunariu N, Yuan W, Carreira S, Plymate SR, Luo J, de Bono JS. Eur Urol. 2019 Nov;76(5):676-685. doi: 10.1016/j.eururo.2019.04.006. Epub 2019 Apr 27.
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 Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. Sharp A, Coleman I, Yuan W, Sprenger C, Dolling D, Rodrigues DN, Russo JW, Figueiredo I, Bertan C, Seed G, Riisnaes R, Uo T, Neeb A, Welti J, Morrissey C, Carreira S, Luo J, Nelson PS, Balk SP, True LD, de Bono JS, Plymate SR. J Clin Invest. 2019 Jan 2;129(1):192-208. doi: 10.1172/JCI122819. Epub 2018 Nov 26. Alternative splicing in prostate cancer. Paschalis A, Sharp A, Welti JC, Neeb A, Raj GV, Luo J, Plymate SR, de Bono JS. Nat Rev Clin Oncol. 2018 Nov;15(11):663-675. doi: 10.1038/s41571-018-0085-0. Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate Cancer. Neeb A, Figueiredo I, Bogdan D, Cato L, Stober J, Jiménez-Vacas JM, Gourain V, Lee II, Seeger R, Muhle-Goll C, Gurel B, Welti J, Nava Rodrigues D, Rekowski J, Qiu X, Jiang Y, Di Micco P, Mateos B, Bielskute S, Riisnaes R, Ferreira A, Miranda S, Crespo M, Buroni L, Ning J, Carreira S, Bräse S, Jung N, Gräßle S, Swain A, Salvatella X, Plymate SR, Al-Lazikani B, Long HW, Yuan W, Brown M, Cato ACB, de Bono JS, Sharp A. Mol Cancer Ther. 2024 Jun 4;23(6):791-808. doi: 10.1158/1535-7163.MCT-23-0354. Development and Validation of a New BAG-1L-Specific Antibody to Quantify BAG-1L Protein Expression in Advanced Prostate Cancer. Neeb A, Figueiredo I, Gurel B, Nava Rodrigues D, Rekowski J, Riisnaes R, Ferreira A, Miranda S, Crespo M, Westaby D, de Los Dolores Fenor de La Maza M, Guo C, Carmichael J, Grochot R, Tunariu N, Cato ACB, Plymate SR, de Bono JS, Sharp A. Lab Invest. 2023 Nov;103(11):100245. doi: 10.1016/j.labinv.2023.100245. Epub 2023 Aug 29. Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC). Welti J, Sharp A, Yuan W, Dolling D, Nava Rodrigues D, Figueiredo I, Gil V, Neeb A, Clarke M, Seed G, Crespo M, Sumanasuriya S, Ning J, Knight E, Francis JC, Hughes A, Halsey WS, Paschalis A, Mani RS, Raj GV, Plymate SR, Carreira S, Boysen G, Chinnaiyan AM, Swain A, de Bono JS; International SU2C/PCF Prostate Cancer Dream Team. Clin Cancer Res. 2018 Jul 1;24(13):3149-3162. doi: 10.1158/1078-0432.CCR-17-3571. Epub 2018 Mar 19. Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer. Sowalsky AG, Figueiredo I, Lis RT, Coleman I, Gurel B, Bogdan D, Yuan W, Russo JW, Bright JR, Whitlock NC, Trostel SY, Ku AT, Patel RA, True LD, Welti J, Jimenez-Vacas JM, Rodrigues DN, Riisnaes R, Neeb A, Sprenger CT, Swain A, Wilkinson S, Karzai F, Dahut WL, Balk SP, Corey E, Nelson PS, Haffner MC, Plymate SR, de Bono JS, Sharp A. Clin Cancer Res. 2022 Aug 15;28(16):3509-3525. doi: 10.1158/1078-0432.CCR-22-0851. JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer. Paschalis A, Welti J, Neeb AJ, Yuan W, Figueiredo I, Pereira R, Ferreira A, Riisnaes R, Rodrigues DN, Jiménez-Vacas JM, Kim S, Uo T, Micco PD, Tumber A, Islam MS, Moesser MA, Abboud M, Kawamura A, Gurel B, Christova R, Gil VS, Buroni L, Crespo M, Miranda S, Lambros MB, Carreira S, Tunariu N, Alimonti A, Al-Lazikani B, Schofield CJ, Plymate SR, Sharp A, de Bono JS; , SU2C/PCF International Prostate Cancer Dream Team. Cancer Res. 2021 Feb 15;81(4):1087-1100. doi: 10.1158/0008-5472.CAN-20-1807. Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer. Sharp A, Welti JC, Lambros MBK, Dolling D, Rodrigues DN, Pope L, Aversa C, Figueiredo I, Fraser J, Ahmad Z, Lu C, Rescigno P, Kolinsky M, Bertan C, Seed G, Riisnaes R, Miranda S, Crespo M, Pereira R, Ferreira A, Fowler G, Ebbs B, Flohr P, Neeb A, Bianchini D, Petremolo A, Sumanasuriya S, Paschalis A, Mateo J, Tunariu N, Yuan W, Carreira S, Plymate SR, Luo J, de Bono JS. Eur Urol. 2019 Nov;76(5):676-685. doi: 10.1016/j.eururo.2019.04.006. Epub 2019 Apr 27.
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 Drug Development Unit Patient and Public Involvement Forum 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Monthly patient and public forum to discuss the running of DDU; ensuring feedback and changes where required.
Year(s) Of Engagement Activity 2024
 
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 Hosted Prostate Cancer Patient 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Hosted patient who reviewed our research program and offered feedback on progress
Year(s) Of Engagement Activity 2023
 
Description Hosted prostate cancer patient at Institute of Cancer Research 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Prostate cancer patient attended lab meeting; gave a talk on his experience with prostate cancer and provided input on our research portfolio.
Year(s) Of Engagement Activity 2023
 
Description Hosted prostate cancer patient at Institute of Cancer Research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Patient provided an hour seminar about living with metastatic prostate cancer. Following which he reviewed our research portfolio and discussed our work offering input from a patient persepctive.
Year(s) Of Engagement Activity 2022
 
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 Institute of Cancer Research Supporter Tea 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Institute of Cancer Research Supporter Tea at which I supported by providing a presentation on work being done at the institute and then discussed with individuals their own experiences and further the work we do.
Year(s) Of Engagement Activity 2022
 
Description Patient and public review of our research 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Visit of three patients/relatives to review our research portfolio providing trainees an opportunity to present projects/science in a lay manner.
Year(s) Of Engagement Activity 2025
 
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 Spoke at Prostate Cancer UK Big Hello 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Presentation to Prostate Cancer UK on the work we do to support their internal training
Year(s) Of Engagement Activity 2023
 
Description Swiss Life Asset Managers UK Annual Charity Fundraiser 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Charitable event raising funds for Institute of Cancer Research. Attended and gave presentation on our work.
Year(s) Of Engagement Activity 2023
 
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