Mechanisms of Radiation-Induced Bladder Toxicity in Prostate Cancer Treatment: Correlation of Urinary Biomarkers with Bladder Pathophysiology

Lead Research Organisation: Queen's University of Belfast
Department Name: Centre for Cancer Res and Cell Biology

Abstract

Radiation therapy is a life-saving treatment for many prostate cancer patients but is associated with adverse side effects. Due to the close proximity of the prostate to the urinary bladder, unavoidable collateral damage to the bladder from the radiation beams means that bladder injury is common. Radiation injury to the bladder is manifested as urinary symptoms of urgency, frequency, nocturia and incomplete bladder emptying. Symptoms occurring during the radiation therapy period often diminish in severity within 3-6 months. However, intolerable bladder dysfunction can develop months or even years after the radiation therapy is completed. Not only is it currently impossible to predict which patients will develop late bladder toxicity, we do not understand the processes underlying bladder damage caused by radiation therapy.

The goal of our proposed project is to define the mechanisms underpinning radiation generated bladder dysfunction using integrated multi-disciplinary approaches. We are currently recruiting prostate cancer patients who will have radiation therapy, to a research clinical trial. Biomarkers of bladder dysfunction in urine samples will be measured before, during and in the 24 months following treatment. Urinary biomarker levels will be correlated with symptoms of bladder dysfunction and impact on health-related quality of life. The Investigator team have complementary expertise in bladder physiology, radiation biology and clinical treatment of prostate cancer and will develop an animal model of radiation therapy, clinically relevant to treatment of prostate cancer patients. We will assess the impact of radiation therapy at specific time points post-treatment on the urinary behaviour of the animals to assess early and late bladder damage. The work will then progress to the organ, tissue, cellular and molecular level as we use a panel of cell physiology, cell biology and cell imaging methodologies to elucidate the mechanisms driving radiation damage in the bladder. The research will enable us to develop strategies to limit radiation damage to the bladder, enabling us to deliver larger, effective radiation doses to maximise tumour kill and minimise radiation bladder toxicity. The biomarker work will enable us to predict which patients are at risk of irreversible late bladder dysfunction and stratify these patients towards radio-protectant therapy.

Technical Summary

Radiation therapy for prostate cancer (PCa) patients is potentially life-saving but is associated with adverse effects. Close proximity of the prostate to the bladder means that unavoidable collateral damage to the bladder commonly leads to bladder dysfunction. Acute effects of radiation induced bladder toxicity (RIBT) during the radiation therapy period often diminish in severity within 3-6 months. However, intolerable bladder dysfunction can develop months or even years after the post-treatment. We cannot currently predict which patients are at risk of late RIBT; furthermore we do not understand the underlying mechanisms.

The proposed project will define the mechanisms underpinning RIBT using integrated multi-disciplinary approaches. We are currently recruiting PCa patients to a research clinical trial. Biomarkers of bladder dysfunction (ATP and neurotrophins) in urine samples will be measured before, during and at follow-up appointments, up to 24 months post-treatment. Urinary biomarker concentrations will be correlated with IPSS/RTOG derived information on bladder toxicity and health-related quality of life. The applicants have complementary expertise in bladder physiology, radiation biology and clinical treatment of PCa. Development of an animal model of clinically relevant, PCa radiation therapy will allow us to assess the manifestation of RIBT during and after radiation at specific time points post-treatment by characterising changes in micturition patterns. The underpinning molecular mechanisms driving cellular remodelling and aberrant contraction will be evaluated employing a panel of cell physiology, cell biology and cell imaging. The research will enable development of strategies to limit radiation damage to the bladder, allowing delivery of larger, effective radiation doses. The biomarker work will enable us to predict which patients are at risk of irreversible late bladder dysfunction and stratify these patients towards radio-protectant therapy.

Planned Impact

1. Who will benefit from this research?

The goal of the present proposal is to define the mechanisms underpinning radiation induced bladder toxicity (RIBT), a clinical condition negatively impacting the health and well-being of patients who have received pelvic radiation therapy for prostate cancer. RIBT is an unavoidable consequence of pelvic irradiation representing collateral damage to normal tissues located close to the tumour site.
Prostate cancer is the most common genitourinary cancer in UK men with many patients undergoing radiation therapy and developing RIBT during treatment and months /years after treatment has ended. It is surprising that research in this area has been overlooked and the major research was 20-30 years ago. Progress with prostate cancer treatment now needs to be matched with improved health-related quality of life of prostate cancer survivors.
Successful realisation of the project's objectives will direct development of strategies enabling the delivery of larger, effective radiation doses to maximise tumour kill and minimise radiation bladder toxicity. We envisage that the impact to patients will be medium-term as the proposal will provide essential data on the cellular mechanisms underpinning RIBT. An important next step would be the development of bladder radioprotective agents. This seems feasible given that our pilot work has demonstrated that the radiosensitive region of the bladder is just below the urothelial lining - radioprotective agents could potentially be delivered intravesically prior to treatment.
The promise of better radiation therapy for pelvic malignancies in combination with bladder radioprotection will be welcomed by patients and their families/carers.
International research groups who work on bladder dysfunction will benefit from this research; we will visit key groups in the EU and the USA during the project to share our findings and discuss the impact for urology translational research.
The commercial private sector, e.g. pharmaceutical companies will benefit from the MRC sponsored research. Fresh thinking and novel avenues of research are urgently needed to drive development of RIBT therapies.
Publicity through the University Media and Communications Centre will bring the issue of RIBT to the attention of the public, health care practitioners and provide new hope to individuals, their families and carers.
Local government policy makers regularly visit CCRCB and will see the benefit of investing in research for the wellbeing of a significant proportion of the electorate who are impacted by cancer and RIBT.
The Northern Ireland Bladder Forum comprises urologists and uro-oncologists who meet annually to discuss advances in the field. The PI is part of the Forum and presents recent research advances. Forum members will be keen to drive translation to the clinic.

2. How will they benefit?
RIBT is a highly prevalent condition which in addition to limiting the effective radiation dose to be given to a pelvic tumour, can destroy an individual's quality of life. Social isolation from a debilitating and embarrassing condition often leads to cessation of gainful employment. The project will significantly advance the field by stratifying and defining the mechanisms underpinning radiation bladder dysfunction, providing a scientific platform for follow-on translational research. A realistic time-scale of 5-8 years for a phase 1 trial is ambitious but feasible at this stage.
The UK government's changes to pension age means that many more people are expected to work until at least age 67. Yet, this is the age where prostate cancer is more prevalent with a significant proportion of people who suffer chronic dysfunctional bladder unable to sustain employment. The benefits of the research project, in the medium term will support cancer survivors working for longer and contributing to the economic wealth of the nation with an improved quality of life.

Publications

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McCloskey KD (2019) The detrusor-free bladder - it can still hold its water. in The Journal of physiology

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McCloskey KD (2017) Is electrolyte transfer across the urothelium important?: ICI-RS 2015. in Neurourology and urodynamics

 
Description British Pharmacological Society Travel Grant NMcK
Amount £326 (GBP)
Organisation British Pharmacological Society (BPS) 
Sector Learned Society
Country United Kingdom
Start 04/2018 
End 04/2018
 
Description PhD Studentship
Amount £51,000 (GBP)
Organisation Queen's University Belfast 
Sector Academic/University
Country United Kingdom
Start 09/2016 
End 09/2019
 
Description Physiological Society Travel Grant
Amount £700 (GBP)
Organisation Physiological Society 
Sector Learned Society
Country United Kingdom
Start 04/2017 
End 04/2017
 
Description Physiological Society Travel Grant KS
Amount £500 (GBP)
Organisation Physiological Society 
Sector Learned Society
Country United Kingdom
Start 09/2017 
End 09/2017
 
Description Physiological Society Travel Grant KS
Amount £500 (GBP)
Organisation Physiological Society 
Sector Learned Society
Country United Kingdom
Start 06/2016 
End 06/2016
 
Description Physiological Society Travel Grant KS
Amount £500 (GBP)
Organisation Physiological Society 
Sector Learned Society
Country United Kingdom
Start 04/2017 
End 04/2017
 
Description Physiological Society Travel Grant NMcK
Amount £500 (GBP)
Organisation Physiological Society 
Sector Learned Society
Country United Kingdom
Start 12/2017 
End 12/2017
 
Description SMDBS School Scholarships KS
Amount £900 (GBP)
Organisation Queen's University Belfast 
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 04/2017
 
Description SMDBS School Scholarships KS
Amount £900 (GBP)
Organisation Queen's University Belfast 
Sector Academic/University
Country United Kingdom
Start 04/2018 
End 04/2018
 
Description SMDBS School Scholarships KS
Amount £400 (GBP)
Organisation Queen's University Belfast 
Sector Academic/University
Country United Kingdom
Start 07/2016 
End 07/2016
 
Description SMDBS School Scholarships NMcK
Amount £150 (GBP)
Organisation Queen's University Belfast 
Sector Academic/University
Country United Kingdom
Start 11/2017 
End 11/2017
 
Description Young Urology Meeting KS
Amount £250 (GBP)
Organisation The International Consultation on Incontinence - Research Society 
Start 10/2015 
End 10/2015
 
Description Young Urology Meeting KS
Amount £200 (GBP)
Organisation The International Consultation on Incontinence - Research Society 
Start 10/2016 
End 10/2016
 
Description SGUL collaboration 
Organisation St George's University of London
Department Molecular and Clinical Sciences Research Institute
Country United Kingdom 
Sector Hospitals 
PI Contribution We investigated the role of hERG channels in bladder contractility with a specific focus on neurogenic and spontaneous contractions. A selective hERG channel blocker, E4031 was found to significantly enhance spontaneous contractions in ex vivo bladder rings and whole bladder pressure-volume experiments.
Collaborator Contribution The SGUL team initiated the study with pilot experiments and following an initial discussion between the PIs in SGUL and QUB in 2016, it was agreed that both teams would investigate this pharmacological study in the future. In 2016-18, the SGUL team carried out in vitro myography, PCR, patch-clamp and protein expression experiments. Following on from this and after discussion of the findings, in 2018, the QUB team carried out the agreed experiments (above) and the data/findings have been reviewed over teleconference between the 2 sites.
Impact We are currently drafting a manuscript of the collaborative study for publication.
Start Year 2016
 
Description UCD Immunometabolism collaboration 
Organisation University College Dublin
Department School of Public Health, Physiotherapy and Population Science
Country Ireland 
Sector Academic/University 
PI Contribution I contacted the PI to discuss a possible collaboration on bladder dysfunction related to obesity, type 2 diabetes and associated inflammation. We held several teleconference and face-to-face meetings in QUB to explore opportunities for grant funding to support a project. In QUB, we provided pilot data on pathophysiology in mouse models of type 2, obesity related diabetes and NLRP3 inflammation. Bladder tissue was sent form UCD to QUB from diet-induced obesity models which were studied in histology protocols. In addition, a colleague from QUB with expertise in inflammation was invited to join the collaboration and from this, further pilot data was generated and a grant application was submitted to MRC PSMB in January 2019.
Collaborator Contribution The UCD team provided tissue from novel diet-induced obesity models of type 2 diabetes along with relevant phenotype data. This tissue was studied in QUB (as above). The UCD team contributed expertise in inflammation related to diet and obesity and will lead a workpackage on the grant application that was submitted by QUB to MRC in Jan 2019, should it be successful.
Impact Grant application submitted to MRC, Jan 2019
Start Year 2017
 
Description Vermont Collaboration 
Organisation University of Vermont
Department Department of Pharmacology
Country United States 
Sector Academic/University 
PI Contribution Expertise in urinary bladder cellular remodelling and bladder physiology. Access to pilot data.
Collaborator Contribution Expertise in bladder physiology, particularly with the newly-released UroVoid platform (recording mouse urination) and PRIM recordings (bladder pressure/volume, live cell imaging and afferent nerve activity). Access to pilot data.
Impact Pilot data has been generated which will potentially lead to a publication and funding application.
Start Year 2017
 
Description Vienna collaboration 
Organisation Medical University of Vienna
Country Austria 
Sector Academic/University 
PI Contribution I have visited Professor Wolfgang Doerr in Vienna and co-hosted his visit to Belfast in relation to the Radiation Bladder project. We are working together on animal models of in vivo radiation. I sent one of my Postdoctoral Research Assistants to the Vienna laboratory to receive relevant in vivo irradiation training.
Collaborator Contribution Professor Doerr's laboratory provided training in small animal irradiation to myself and my postdoctoral research assistant. As an international expert, Professor Doerr also acts as a consultant on our animal experiment design.
Impact No publications yet.
Start Year 2014
 
Description Washington collaboration 
Organisation Fred Hutchinson Cancer Research Center (FHCRC)
Country United States 
Sector Charity/Non Profit 
PI Contribution I provided intellectual input on CaV1.3 ion channel physiology and pharmacology and shared pre-clinical data on CaV1.3 and prostate cancer.
Collaborator Contribution Professor Janet Stanford and Dr Milan Geybels work in the area of Epidemiology/Public Health and are interested in the use of calcium channel blockers and associated risks/outcomes for prostate cancer patients.
Impact Geybels MS, McCloskey KD, Mills IG, Stanford JL. Calcium Channel Blocker Use and Risk of Prostate Cancer by TMPRSS2:ERG Gene Fusion Status. Prostate. 2017 Feb;77(3):282-290. doi: 10.1002/pros.23267. Epub 2016 Oct 18. This publication is multidisciplinary - the study is epidemiological in origin, some of the discussion/interpretation also encompasses cell physiology.
Start Year 2015
 
Description Biology Week October 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Co-organised and participated in 'Biology Week' at Wallace High School. Organised and participated in a structured Q&A session on Biology careers to A-Level Biology students.
Year(s) Of Engagement Activity 2018
URL https://www.wallacehigh.org/news/bake-off-takes-a-biological-twist/
 
Description CCRCB Open Day 
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 Public/other audiences
Results and Impact The Centre for Cancer Research and Cell Biology holds an annual Open Day for members of the public, patients and fundraisers to visit the Centre, meet the scientists and engage with the ongoing research. In 2017, the Open Day was also part of the Northern Ireland Science Festival. The aim of the activities run by myself and my group was to discuss our research with the visitors. This has taken the form of a short presentation (15 min) followed by Q&A, laboratory tours where we demonstrated live-cell signaling and 3D-confocal microsopy and 'Meet the Scientist' conversations which involved speaking with small groups (6-8 people in each) about our research into radiation bladder toxicity. In all cases, there was substantial discussion particularly with patients affected by the conditions or by family members. It was particularly rewarding to see people relating their own experience to the science in our laboratory. A number of school children attended who were interested in pursuing a career in medicine/life sciences; several conversations ensued around career advice and planning.

In 2018, we developed this activity to include 3D models of bladder fullness using water-filled balloons and measuring cylinders.
Year(s) Of Engagement Activity 2015,2016,2017,2018
URL https://www.qub.ac.uk/corporate-plan/innovation-impact/News/CCRCBOpenDay2018.html
 
Description Hosted Nuffield Student (BT) - several presentations 
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 Schools
Results and Impact The PI hosted a Nuffield Student on a summer research placement for 5 weeks during July-August 2018. At the end of the event, the University hosted an event for all Nuffield students across Northern Ireland, their teachers and parents. The PI and the Student gave separate presentations to this event.

As a result of this, the Student applied to present at the Royal Society Schools Research Conference and was selected as the only Northern Ireland student to present. We attended the Royal Society Conference and the student presented his work throughout the day. (London, December 2018)
Year(s) Of Engagement Activity 2018
URL https://twitter.com/SentinusNI/status/1031529720410775554
 
Description Hosting School Visits 
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 KD McCloskey has led a programme on Engagement with Schools 'From Discovery to Recovery' which engages pupils in learning about Cancer Research. This iniatitive was underpinned by an RCUK grant to QUB 'Inspiring Lives - Creating Futures',of which KD McCloskey is a co-Investigator. The purpose of this Schools Universities Partnership Initiative (SUPI) was to introduce school pupils (year 9/10) to research and help inform choices for GCSE subjects at the end of Year 10. Events were organised for pupils and their teachers including visiting the laboratories, carrying our experiments, entering poster competitions and completing quizzes. We also visited schools, carrying out science workshops and presenting at careers conventions.
Year(s) Of Engagement Activity 2015,2016
URL https://www.qub.ac.uk/sites/SUPI/
 
Description Hosting workshadowing students 
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 Each year, 1-2 pupils from schools in Northern Ireland were hosted on Workshadowing/Workplacement activities in our laboratory. Feedback has been very positive and a number of pupils have gone on to study medicine at university.
Year(s) Of Engagement Activity 2015,2016,2017,2018
 
Description RCUK Workshop: Reimagining Schools University Partnership Initiatives 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Along with several colleagues, I was invited to present at the RCUK Reimagining Schools and University Partnerships Initiatives (SUPI) event in London, October 5, 2017. The aim of the presentation was to share good practice from our public engagement and discuss outcomes. Another aim was to learn from other teams involved in the SUPI project and also to engage with pupil representatives who were invited to the event. Following on from this, we have further developed our SUPI programme in the University and will continue to engage with School pupils.
Year(s) Of Engagement Activity 2017
URL https://www.publicengagement.ac.uk/events/reimagining-school-university-partnerships-supi-programme
 
Description Schools University Partnership Initiative 
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 Postgraduate students
Results and Impact The PI led a team of 4 PhD students and Postdoctoral Fellows to a School in Northern Ireland which was part of an Area Learning Community (ALC). The ALC arranged for pupils from 4 Schools to attend our 'Cancer Research - From Discovery to Recovery' laboratory classes in June 2018. Around 90 pupils and their teachers attended and participated in activities including DNA extraction from strawberries, building DNA models from Jelly Babies and an interactive quiz on cancer biology.

Feedback was very positive and in October 2018, the pupils and teachers came to QUB to take part in a follow up session in our teaching laboratories 'Detecting Cancer in Cells and Patients'. A larger team of PhD students, Postdoctoral Fellows and research technicians supported the event that was led by the QUB PI. Again, feedback was positive.

Following on from this, pupils entered a poster competition that was hosted in QUB in December 2018.
Year(s) Of Engagement Activity 2018
URL https://www.qub.ac.uk/sites/SUPI/AboutUs/