Molecular determinants of Radiosensitivity
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
Radiation remains second only to surgery in curing cancer, but there is wide variation from patient to patient is the effectiveness of radiation treatment. Some of this is due to the fact that some cancers are much more sensitive to radiation treatment than others. We aim to try to discover what causes this difference in effectiveness to see whether we could find drugs that could be used with radiation to make the cancers more sensitive to treatment. If successful this could increase our chance of curing the cancer and might even allow us to use lower doses of radiation to achieve the maximum effect.
Technical Summary
Significant gains in the therapeutic ratio of radiotherapy could be made if treatments could be developed that selectively rendered tumour cells specifically more sensitive to IR without altering the sensitivity of normal tissues. We plan to identify clinically exploitable targets that may enable tumours to be made more sensitive to radiotherapy using siRNA screens.
We will screen a druggable genome library using HeLa cells, and a library of 800 kinase genes using NSCLC cell lines containing specific mutations. The aim is to identify novel genes whose depletion induces tumour-specific radiosensitisation. The clinical significance of those genes confirmed as being involved in tumour cell radioresistance will be assessed by correlating the clinical outcomes of retrospective series of cancer patients with the tumour RNA expression levels of these genes.
We will also continue to investigate the mechanism of action of a gene (POLQ) that we have recently been shown to be involved in tumour cell radiosensitivity. We have previously shown that tumour cells depleted of POLQ are rendered more sensitive to ionising radiation and chemotherapy as a result of reduced homologous recombination efficiency. The structural basis for this will be examined using truncated POLQ constructs to determine which parts of POLQ are involved in altering radiosensitivity. This may enable us to identify which parts of POLQ could be targeted pharmacologically to inhibit POLQ.
The future plans also focus on understanding the mechanisms that lead to vascular normalisation and decreased hypoxia in tumours after PI3K/mTOR inhibtition and determining whether these events occur in human tumours. We propose two approaches.
We will evaluate the time course of changes in hypoxia and perfusion after inhibitor treatment. We know that approximately 75% of the improvement in perfusion and oxygenation has occurred by 72h. We will now evaluate the changes at earlier times along with evaluation of drug efficacy based on IHC at these times. We will also determine the reversibility of the events after drug withdrawal. Knowing the timing of the changes will allow us to determine whether alterations in vascular morphology for example precede or follow changes in oxygenation.
We will determine whether the increased oxygen level after inhibition of PI3K might be due to decreased oxygen consumption using tissue culture and spheroid models. At the same time we will measure ATP levels, lactate and pH after drug treatment. If there are detectable shifts we will also measure other key metabolites.
We will screen a druggable genome library using HeLa cells, and a library of 800 kinase genes using NSCLC cell lines containing specific mutations. The aim is to identify novel genes whose depletion induces tumour-specific radiosensitisation. The clinical significance of those genes confirmed as being involved in tumour cell radioresistance will be assessed by correlating the clinical outcomes of retrospective series of cancer patients with the tumour RNA expression levels of these genes.
We will also continue to investigate the mechanism of action of a gene (POLQ) that we have recently been shown to be involved in tumour cell radiosensitivity. We have previously shown that tumour cells depleted of POLQ are rendered more sensitive to ionising radiation and chemotherapy as a result of reduced homologous recombination efficiency. The structural basis for this will be examined using truncated POLQ constructs to determine which parts of POLQ are involved in altering radiosensitivity. This may enable us to identify which parts of POLQ could be targeted pharmacologically to inhibit POLQ.
The future plans also focus on understanding the mechanisms that lead to vascular normalisation and decreased hypoxia in tumours after PI3K/mTOR inhibtition and determining whether these events occur in human tumours. We propose two approaches.
We will evaluate the time course of changes in hypoxia and perfusion after inhibitor treatment. We know that approximately 75% of the improvement in perfusion and oxygenation has occurred by 72h. We will now evaluate the changes at earlier times along with evaluation of drug efficacy based on IHC at these times. We will also determine the reversibility of the events after drug withdrawal. Knowing the timing of the changes will allow us to determine whether alterations in vascular morphology for example precede or follow changes in oxygenation.
We will determine whether the increased oxygen level after inhibition of PI3K might be due to decreased oxygen consumption using tissue culture and spheroid models. At the same time we will measure ATP levels, lactate and pH after drug treatment. If there are detectable shifts we will also measure other key metabolites.
People |
ORCID iD |
W Gillies McKenna (Principal Investigator) |
Publications
Corroyer-Dulmont A
(2017)
Improved outcome of 131I-mIBG treatment through combination with external beam radiotherapy in the SK-N-SH mouse model of neuroblastoma.
in Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
Fokas E
(2013)
A treatment planning comparison of four target volume contouring guidelines for locally advanced pancreatic cancer radiotherapy.
in Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
Al-Assar O
(2016)
The radiosensitizing effects of Nelfinavir on pancreatic cancer with and without pancreatic stellate cells.
in Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
Al-Assar O
(2014)
Contextual regulation of pancreatic cancer stem cell phenotype and radioresistance by pancreatic stellate cells.
in Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
Higgins GS
(2016)
Personalized Radiation Oncology: Epidermal Growth Factor Receptor and Other Receptor Tyrosine Kinase Inhibitors.
in Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer
Jones B
(2012)
Dilemmas concerning dose distribution and the influence of relative biological effect in proton beam therapy of medulloblastoma.
in The British journal of radiology
Gill MR
(2017)
Targeted radionuclide therapy in combined-modality regimens.
in The Lancet. Oncology
Falzone N
(2018)
Dosimetric evaluation of radionuclides for VCAM-1-targeted radionuclide therapy of early brain metastases.
in Theranostics
Description | AACR Annual Meeting Program Committee |
Geographic Reach | North America |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | AACR Colon Cancer Research Fellowships Scientific Review Committee |
Geographic Reach | North America |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | AACR Radiation Biology Section of the Tumor Biology Subcommittee 2014 |
Geographic Reach | North America |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | AACR Radiation Oncology Task Force |
Geographic Reach | North America |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Advisory role to facilitate the development of AACRs programs and initiatives related to radiation oncology |
Geographic Reach | North America |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | CR-UK Research Strategy Committee |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Chair of the Scientific Advisory Board for the University Cancer Center, Dresden, Germany |
Geographic Reach | Europe |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Institut Universaire du Cancer, Toulouse, France Scientific Advisory Board |
Geographic Reach | Europe |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | International Scientific Advisory Board of Institut Curie, Paris, France |
Geographic Reach | Europe |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | NCRI Radiotherapy Radiobiology Rapid Review Group |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Scientific Advisory Board of the German Cancer consortium (DKTK) |
Geographic Reach | Asia |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Application for support to create a precision medicine research team to undertake translational and clinical research to improve treatment for pancreatic cancer |
Amount | £390,060 (GBP) |
Organisation | Kidani Memorial Trust |
Sector | Charity/Non Profit |
Country | Japan |
Start | 06/2014 |
End | 06/2017 |
Description | Early Phase Oncology Trial Infrastructure |
Amount | £563,390 (GBP) |
Funding ID | ONC1516/01 |
Organisation | Oxford University Hospitals NHS Foundation Trust |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2015 |
End | 03/2016 |
Description | Equipment allocation |
Amount | £125,000 (GBP) |
Funding ID | C5255/A12331 |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2010 |
End | 03/2013 |
Description | Oxford CRUK (OCRC) |
Amount | £4,081,374 (GBP) |
Funding ID | C38302/A12278 |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2010 |
End | 06/2013 |
Description | Oxford CRUK Training |
Amount | £742,823 (GBP) |
Funding ID | C38302/A12450 |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2011 |
End | 09/2015 |
Description | Cancer drug discovery |
Organisation | Cancer Research Technology (CRT) |
Country | United Kingdom |
Sector | Private |
PI Contribution | Identification of a clinically exploitable drug target (POLQ). We are now collaborating on the preclinical testing of lead compounds. |
Collaborator Contribution | Development of chemical inhibitors. With the support of the team in Oxford CRT have obtained a commercial partner for future work. |
Impact | No academic output yet |
Start Year | 2012 |
Description | The generation of novel mitochondrial complex 1 inhibitors that relieve tumour hypoxia |
Organisation | University of Oxford |
Department | Department of Chemistry |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Our lab will perform three experiments to evaluate complex 1 inhibitory fenofibrate derivatives generated by the Chemistry lab. 1) Do compounds reduce the oxygen consumption rate of cancer cells? ii) Do the compounds alleviate spheroid hypoxia? iii) Do the compounds alleviate tumour hypoxia? |
Collaborator Contribution | See above |
Impact | Initial test compounds were tested for their ability to reduce oxygen consumption. Two compounds of interest were identified and will be further modified by the Chemistry lab (Chris Schofield). Disciplines: Radiation Oncology (McKenna) and Chemistry (Schofield). Three sets of comp`ounds have now been generated and tested for their potential to reduce the OCR, with several promising compounds identified. |
Start Year | 2015 |
Description | Alpha particles used to trear prostate cancer that has spread to bone |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Paper Presentation |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | N/A |
Year(s) Of Engagement Activity | 2012 |
Description | Alpha radiation treats prostate cancers |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Paper Presentation |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | N/A |
Year(s) Of Engagement Activity | 2012 |
Description | Article in Oxford Mail |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Group of scientists bringing science to the public Monthly meeting The members of the public who attended are now more aware of the areas of science that were discussed. |
Year(s) Of Engagement Activity | 2011 |
Description | BBC radio interview on the Today programme |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Interview on the Today programme |
Year(s) Of Engagement Activity | 2015 |
Description | BBC radio interview on the Today programme |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Supporters |
Results and Impact | October 2013, Interview with Tom Feilden, science correspondent for the Today programme heard by anyone listening to the Today programme on BBC radio 2 |
Year(s) Of Engagement Activity | 2013 |
Description | CRUK filming |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Taking part in a short documentary film for CRUK to present to members o the public to assist with fundraising due to be released December 2013 |
Year(s) Of Engagement Activity | 2013 |
Description | Cancer victims welcome £138m research centre |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Paper Presentation |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | N/A |
Year(s) Of Engagement Activity | 2012 |
Description | Centre will see city lead the world in cancer care |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Paper Presentation |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | N/A |
Year(s) Of Engagement Activity | 2012 |
Description | Current limitations of radiotherapy imaging and the future role of functional imaging |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | National |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | presenting at Oncology RCR Annual meeting presentation followed by discussion session |
Year(s) Of Engagement Activity | 2013 |
URL | http://www.rcr.ac.uk/docs/oncology/pdf/Onc_AnnualMeeting.pdf |
Description | Is spending on proton beam therapy for cancer going too far too fast? |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Paper Presentation |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | N/A |
Year(s) Of Engagement Activity | 2012 |
Description | MP visit to Professor McKenna |
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 | Policymakers/politicians |
Results and Impact | N/A The visit updated the MP about the activities in the Department of Oncology |
Year(s) Of Engagement Activity | 2014 |
Description | Major Donor Visit |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Supporters |
Results and Impact | Sept 2013, presentation to existing major donor On going discussions for potential funding |
Year(s) Of Engagement Activity | 2013 |
Description | Major Donor Visit hosted by Professor McKenna and others |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Major donor visit hosted with other key scientists and clinicians This visit helped inform the donor |
Year(s) Of Engagement Activity | 2014 |
Description | Major Donor visit |
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 | Supporters |
Results and Impact | January 2013 Major Donor visit, hosted together with other key scientists and clinicians Interaction with potential high level donors |
Year(s) Of Engagement Activity | 2013 |
Description | Mirada Medical excites AAPM with latest additions to RTxSoftware |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Paper Presentation |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | N/A |
Year(s) Of Engagement Activity | 2012 |
Description | New Prostate cancer treatment may reduce side effects |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Paper Presentation |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | N/A |
Year(s) Of Engagement Activity | 2012 |
Description | New techniques and personalised treatment in Radiotherapy |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Type Of Presentation | Paper Presentation |
Geographic Reach | International |
Primary Audience | Health professionals |
Results and Impact | N/A |
Year(s) Of Engagement Activity | 2012 |
Description | Presenting at local MPs Labour Party meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Policymakers/politicians |
Results and Impact | Talk was very well received and sparked interest |
Year(s) Of Engagement Activity | 2015 |
Description | Press launch for Precision Cancer Medicine Institute |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Local BBC TV, Local BBC Radio, Jack FM, Oxford Mail The press launch resulted in many enquiries |
Year(s) Of Engagement Activity | 2014 |
Description | Prof Gillies McKenna giving the Frank Ellis Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | on line presentation open to everyone on the www Open to all |
Year(s) Of Engagement Activity | 2013 |
URL | http://twitter.com/RCRadiologists/status/339734619660374017 |
Description | Prof Gillies McKenna to head new world-leading cancer research centre |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Paper Presentation |
Geographic Reach | Local |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | N/A |
Year(s) Of Engagement Activity | 2012 |
Description | Professor McKenna - BBC Radio 4 Interview with Paddy O'Connell |
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 | Media (as a channel to the public) |
Results and Impact | The interview created increased interest N/A |
Year(s) Of Engagement Activity | 2014 |
Description | Professor McKenna presenting the David Skeggs Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | National |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Talk sparked questions and discussion afterwards Acknowledgement of work |
Year(s) Of Engagement Activity | 2014 |
Description | Professor McKenna's talk to Department of Oncology |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | The talk created more interest N/A |
Year(s) Of Engagement Activity | 2014 |
Description | Proton NHS event |
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 | Professional Practitioners |
Results and Impact | This was an event to inform clinicians at the Oxford University Hospitals NHS Trust about the Precision Cancer Medicine Institute |
Year(s) Of Engagement Activity | 2015 |
Description | The Tumour Microenvironment in Radiotherapy. Approaches to the Problem |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | multidisciplinary symposium entitled "New Cancer Targets (NCT) on September 23-24th, 2013, in Heidelberg. Germany. presentation and discussion |
Year(s) Of Engagement Activity | 2013 |
URL | http://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=107&ved=0CEgQFjAGOGQ&url=http%3A%2F%2... |
Description | The future of targeted cancer therapy |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | 5th & 6th July 2013 Plenary lecture presentation followed by discussion |
Year(s) Of Engagement Activity | 2013 |
URL | http://www.uni-due.de/imperia/md/content/medizin/de/studium/retreat_2013_grk_1739.pdf |
Description | Two new cancer research centres to open in Oxford |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Paper Presentation |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | N/A |
Year(s) Of Engagement Activity | 2012 |
Description | Why do we still use radiation to treat cancer? |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Regional |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | 24 June 13 invited seminar speaker, then hosted to meet other academics in Glasgow formed new contacts |
Year(s) Of Engagement Activity | 2013 |