Role of the endogenous signalling regulator Similar Expression to FGF (Sef) in growth factor signalling in prostate cancer

Lead Research Organisation: University of Cambridge
Department Name: Clinical Oncology

Abstract

Targeting growth factors in prostate cancer

Prostate cancer is the commonest male malignancy in the UK (35000 new cases/year). Despite treatment including surgery, many patients will develop a lethal form of disease known as castration resistant prostate cancer. This process is driven in part by molecules called growth factors. We are investigating a gene called Sef which functions as a strong natural inhibitor of growth factors. Our aim is to test if increasing Sef in prostate tumours can enhance treatment designed to block growth factors. If successful, this will offer a new way to treat men with otherwise fatal prostate cancer.

Technical Summary

Background: The EGF, IGF and FGF axis have been strongly implicated in prostate carcinogenesis and tumour progression. Clinical trials of growth factor based therapies however, have so far been disappointing. This may be due to the presence of endogenous signalling regulators such as Similar expression to FGF (Sef), which has been shown to be an important feedback inhibitor of the FGF signalling pathway. Work in our group and others have shown that Sef acts at the level of the Receptor-Ras-MAPK interface to block FGF signalling. This central point of function would predict that Sef can modulate other growth factors besides FGF.
Aims and objectives: To comprehensively evaluate the function of Sef in the prostate cancer cell‘s response to different growth factors and its value as a potential therapeutic target.
Hypothesis: We hypothesize that Sef is a key factor in determining the prostate cancer cell response to different growth factors including the EGF and IGF axis.
Materials and methods: LNCaP, LN3, PC3, PC3M and DU145 prostate cancer cell lines will be used in this study. Endogenous levels of Sef will be manipulated by transfecting cells with Sef cDNA or using siRNA techniques. Changes in transcriptional target activation of EGF and IGF pathways will be assessed using quantitative PCR, Western blotting and luciferase reporter systems. Commercially available FGF, EGF and IGF inhibitors will be used to assess the cell response to different concentrations of growth factor stimulation of FGF, EGF and IGF. These cells will also be subjected to irradiation and the proliferative, invasive and clonogenic response of Sef manipulated cells will be assessed and compared to controls. Apoptosis will be measured using FACS analysis with Annexin V staining and by analysis of PARP cleavage and Caspase 3 levels by western blotting.
Anticipated results: We anticipate Sef to be a key regulator of the EGF/IGF and FGF signalling pathways in prostate cancer and that it slows wn the development of castration resistance of prostate cancer cells. We also anticipate that overexpression of Sef in prostate cancer cells treated with radiotherapy will result in an enhanced apoptosis of these cells.
Scientific/medical opportunities and implications of the study: By over-expressing Sef in prostate cancer cells, we envisage that men treated with growth factor inhibitors with or without adjuvant cytotoxic therapies will result in an enhanced response to these agents and present a novel way in which to treat men with advanced prostate cancer.
 
Description Innovation for Patient Benefit Award
Amount £40,000 (GBP)
Organisation Addenbrooke's Charitable Trust (ACT) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 04/2020
 
Description Joint MRC / The Prostate Cancer Charity Clinical Research Training Fellowship
Amount £60,000 (GBP)
Funding ID CRTF10-02 
Organisation Prostate Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2011 
End 03/2013
 
Description Raymond and Beverly Sackler Studentship 2010-2011
Amount £750 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 04/2011 
End 03/2012
 
Description Partnership with Addenbrooke's Hospital Histopathology and Tissue Bank Department 
Organisation Addenbrooke's Hospital
Department Histopathology Department
Country United Kingdom 
Sector Hospitals 
PI Contribution As a result of this partnership, we have been able to establish a tissue microarray of patients with prostate cancer that is linked to clinical outcome data. We have been responsible in collecting the prostatic biopsy samples and the clinical data.
Collaborator Contribution Our partners produced the tissue TMA from the prostatic biopsy samples that we obtained. T
Impact It is anticipated that the partnership will allow us to investigate whether the protein of my interest Sef, can also act as a biomarker of treatment response in patients with prostate cancer undergoing ADT, Radiotherapy or Surgery. This collaboration has now materialised further and has become an active part of the Cambridge Academic Urology Group.
Start Year 2012
 
Description Partnership with Cambridge Academic Urology Group. 
Organisation University of Cambridge
Department Department of Oncology
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been appointed as an Academic Clinical Lecturer in Urology at the University of Cambridge. As a result of this appointment, I have been working in partnership with the Cambridge Academic Urology Group (AUG) headed by Dr Vincent Gnanapragasam.
Collaborator Contribution The Cambridge AUG has an active portfolio of translational clinical research in prostate cancer. They work in close collaboration with a number of research groups including the Addenbrooke's Tissue Bank, department of Oncology as well as the Wellcome Trust Sanger Institute. I have worked closely as a study lead in a number of projects with the Academic Urology Group.
Impact During my time at the Academic Urology Group, I was the study lead of a multi-centre clinical trial investigating the utility of PSA isoforms (proPSAs) in patients undergoing MRI and prostate biopsies for investigation of suspected prostate cancer. The aim of this trial is to investigate whether the phi test is a more accurate diagnostic test than the current standard of care (PSA and MRI) for prostate cancer). This study is currently ongoing with 4 national centres contributing to the data collection for this study. In addition, I was the recipient of the Addebrooke's Charitable Trust Innovation of Patient Award as a result of this project (2018).
Start Year 2016
 
Description Partnership with Uro-oncology group at the CRUK Cambridge Research Institute 
Organisation Cancer Research UK Cambridge Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution The aims of the CRUK CRI Uro-oncology group overlaps with my project, which is to identify novel ways to treat patients with advanced prostate cancer. It is therefore anticipated that the results of my research will also directly benefit he research undertaken by my collaborator.
Collaborator Contribution As a result of this partnership, I am now able to access the facilities, as well as the technical expertise that is available at the CRUK Cambridge Research Institute (CRI).
Impact As a direct result of this partnership, I was able to access the facilities available at the CRI. Genomics, Immunohistochemistry and Bioinformatic support were some of the examples of facilities that was available. As a result of this collaboration, I was able to perform sophisticated microarray experiments with the backing of the Genomics and Bioinformatics. The collaboration ended in 2014 as a result of the departure of CRUK Cambridge Institute's Uro-oncology group leader Professor David Neal in 2014.
Start Year 2011
 
Description Prostate Cancer UK Scottish Research Event 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact I was invited to give a talk on my funded project to the PCUK Scottish Event, which included a number of distinguished academics in the field of prostate cancer attending the meeting.

Generated interest in my research activity and enquiries for possible collaboration with a Scottish research group.
Year(s) Of Engagement Activity 2013
 
Description The Royal College of Surgeons of England Careers evening 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Schools
Results and Impact Approximately 100 students from various schools across Hertfordshire attended this RCS careers event. All were sixth formers interested in applying for a career in medicine.

Students appear to have become inspired with a career in medicine, particularly Surgery.
Year(s) Of Engagement Activity 2011
 
Description The Royal College of Surgeons of England Fundraising Events 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Supporters
Results and Impact On average, there were approximately 100-200 people attending each of these events. The biggest event was marked by the presence of approximately 500 people in Lonodn.

As a direct result of these fund-raising activities, the Royal College of Surgeons of England have been able to increase the number of surgical research fellowships awarded each year.
Year(s) Of Engagement Activity 2010,2011,2012