Molecular Therapy
Lead Research Organisation:
MRC London Institute of Medical Sciences
Abstract
The new generation of therapies including gene therapy and therapies that attack processes that drive cancer present tremendous challenges in their development. The Molecular Therapy Programme is researching on new enabling technologies involving PET imaging that will provide the opportunity to develop such therapies efficiently. To do this we are injecting radiotracers - compounds containing radioactive tags on them - to specifically image virus delivery, as well as biological activity within the tumours. Although cancer patients will be studied, the technologies being developed/validated, as well as the biological processes being imaged in within the programme are sufficiently generic to find utility in other clinical disciplines.
Technical Summary
This programme has established a Molecular Therapy group to develop and validate PET imaging methodologies in pre-clinical disease models and humans. We are using cancer as disease model with which to assess the pharmacology of imaging agents. The initial focus is on the assessment of gene expression, and anti-proliferative activity of gene directed therapies, viral and non-viral. The human sodium iodide symporter reporter gene (hNIS) system together with Na[124I as well as bioluminescence methods are being explored to establish viral delivery. Furthermore, the biological activity of novel anti-cancer therapies are being examined for inhibition of proliferation in tumours (with [18F]fluorothymidine). Another area of interest is assessing mechanisms of action including induction of inflammation (with [11C]PK11195), pathway specific-imaging for mitogen activated protein kinase activity and angiogenesis. We aim to determine whether these radiotracers measure the biological processes for which they are intended to measure in an accurate, quantitative and reproducible manner. Although the studies will be done in cancer patients, the technologies should be widely applicable to other clinical areas of research; cancer offers a unique way of validating the radiotracers. The research outcomes will be published to enable use by scientists in academia and industry. The methods will play a major role in translation research programmes to develop new therapeutics and hence should have commercial and collaborative potential. We will iterate the pre-clinical and clinical programmes in a unique way to enhance the scientific value of the programme.
Publications

Chan F
(2007)
Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity.
in Molecular cancer therapeutics

Chapon C
(2009)
An in vivo multimodal imaging study using MRI and PET of stem cell transplantation after myocardial infarction in rats.
in Molecular imaging and biology

Contractor K
(2012)
Monitoring early response to taxane therapy in advanced breast cancer with circulating tumor cells and [(18)F] 3´-deoxy-3´-fluorothymidine PET: a pilot study.
in Biomarkers in medicine

Contractor K
(2011)
Use of [11C]choline PET-CT as a noninvasive method for detecting pelvic lymph node status from prostate cancer and relationship with choline kinase expression.
in Clinical cancer research : an official journal of the American Association for Cancer Research

Contractor K
(2012)
Imaging of cellular proliferation in liver metastasis by [18F]fluorothymidine positron emission tomography: effect of therapy.
in Physics in medicine and biology

Contractor KB
(2009)
[11C]choline positron emission tomography in estrogen receptor-positive breast cancer.
in Clinical cancer research : an official journal of the American Association for Cancer Research

Contractor KB
(2011)
[18F]-3'Deoxy-3'-fluorothymidine positron emission tomography and breast cancer response to docetaxel.
in Clinical cancer research : an official journal of the American Association for Cancer Research

Contractor KB
(2009)
Monitoring predominantly cytostatic treatment response with 18F-FDG PET.
in Journal of nuclear medicine : official publication, Society of Nuclear Medicine

Contractor KB
(2012)
Evaluation of limited blood sampling population input approaches for kinetic quantification of [18F]fluorothymidine PET data.
in EJNMMI research

Contractor KB
(2011)
Biological basis of [¹¹C]choline-positron emission tomography in patients with breast cancer: comparison with [¹8F]fluorothymidine positron emission tomography.
in Nuclear medicine communications
Description | Cancer Research UK New Agents Committee (UK) |
Geographic Reach | National |
Policy Influence Type | Participation in advisory committee |
Description | French National Cancer Institute |
Geographic Reach | Asia |
Policy Influence Type | Participation in advisory committee |
Description | Multi-disciplinary Advisory Committee on Non-Invasive Imaging Studies (USA) |
Geographic Reach | North America |
Policy Influence Type | Participation in advisory committee |
Description | National Cancer Institute, Quantitative Imaging Study Section (USA) |
Geographic Reach | North America |
Policy Influence Type | Participation in advisory committee |
Description | National Cancer Research Institute PET Research Steering committee (UK) |
Geographic Reach | National |
Policy Influence Type | Participation in advisory committee |
Description | National Cancer Research Institute Translational Clinical Studies Group (UK) |
Geographic Reach | National |
Policy Influence Type | Participation in advisory committee |
Description | Teaching |
Geographic Reach | Asia |
Policy Influence Type | Influenced training of practitioners or researchers |
Title | Kinetic Spatial Filter |
Description | New temporal intensity information based voxel clustering approach - kinetic spatial filter (KSF) - that reduces the signal from the normal liver whilst retaining signal from tumours |
Type Of Material | Technology assay or reagent |
Year Produced | 2012 |
Provided To Others? | Yes |
Impact | We have published this technique having created it using scan data collected from MRC historical and currently funded work. This has been published (PMID: 20071760) and is now being implimented on new trials to provide proof of viability as a clinical tool. |
URL | http://europepmc.org/abstract/MED/20071760 |
Title | New model for prediction of drug distribution - temozolomide |
Description | Difficulties in direct measurement of drug concentrations in human tissues have hampered the understanding of drug accumulation in tumors and normal tissues. We propose a new system analysis modeling approach to characterize drug distribution in tissues based on human positron emission tomography (PET) data. The PET system analysis method was applied to temozolomide, an important alkylating agent used in the treatment of brain tumors, as part of standard temozolomide treatment regimens in patients. The system analysis technique, embodied in the convolution integral, generated an impulse response function that, when convolved with temozolomide plasma concentration input functions, yielded predicted normal brain and brain tumor temozolomide concentration profiles for different temozolomide dosing regimens (75-200 mg/m2/d). |
Type Of Material | Model of mechanisms or symptoms - human |
Provided To Others? | No |
Impact | The method is considered a robust tool to analyze and predict tissue drug concentrations to help select the most rational dosing schedules. |
Title | Scan data sets |
Description | Data sets from scanned subject cohorts |
Type Of Material | Biological samples |
Year Produced | 2006 |
Provided To Others? | Yes |
Impact | Material allowing improved modelling techniques to be developed for analysis. |
Description | GE Healthcare Imanet |
Organisation | Bayer |
Department | Bayer HealthCare |
Country | Germany |
Sector | Private |
PI Contribution | Practical and intellectual input, faciliteis and equipment plus staff. |
Collaborator Contribution | Practical and intellectual input, plus access to specialist facilities. |
Impact | Publications: 19773436, 19706823, 19049429, 18794263, 18483090. Also two patents. |
Description | Imanova |
Organisation | Imanova |
Country | United Kingdom |
Sector | Private |
PI Contribution | We have provided personnel to allow the transition of tracers we have developed into First in Man studies. |
Collaborator Contribution | We have been able to use the very high level radiochemistry development labs. |
Impact | None as yet |
Start Year | 2012 |
Description | 'A' Level Careers 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 | 6 students from the region visited to talk to researchers in the lab regarding future career choices and aspirations. Students were given a visit to the lab and researcher told them of their experiences at University to help the students decide if this was the right choice for them. We now have close links to a number of schools in the region and will be hosting future visits to encourge participation in science. |
Year(s) Of Engagement Activity | 2012 |
Description | 'Race-for-life' London, UK, 2010 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Members of the public were made more ware of the scientific research being undertaken in Cancer. Nothing quantifiable to date. |
Year(s) Of Engagement Activity | 2010 |
Description | A Level Student work Experience |
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 | Schools |
Results and Impact | Three A Level students were hosted on week work experience visits. The A Level students were able to appreciate the potential of studying science at University and going into a scientific career. |
Year(s) Of Engagement Activity | 2011 |
Description | BRC Public Discussion |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Local Health Professinoals and members of the public who are interested in the research here at Hammersmith Hospital as funded via the BRC initiative attended an afternoon of presentations where they could become better informed about the research and discuss this with the BRC Theme Leads. Local Healthcare Professionals and patients are more aware of the research being undertaken at Hammersmith. |
Year(s) Of Engagement Activity | 2011 |
Description | CRUK Donor Visit |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Tour and explanation of research work and facilites given to donor to CRUK None to date |
Year(s) Of Engagement Activity | 2009 |
Description | Nuffield Bursary Students |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | 4 students worked in the laboratory on a project for between 2 and 6 weeks. Students were awarded a British Science Association Gold Crest Award for their individual projects that they submitted on teh work they had undertaken in the lab. |
Year(s) Of Engagement Activity | 2012 |
Description | Summer A Level student |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Participant in Post-16 Nuffield Foundation Summer Studentships Programme - an 'A' Level student was given hands-on experience of working in a laboratory research setting for 4 weeks during the school holidays. Repeated annually A potential future scientific researcher was engaged with science more closely than usually possible. |
Year(s) Of Engagement Activity | 2009,2011,2013,2014,2015 |
Description | Summer student |
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 | An 'A' level school student was given hands-on experience of working in a laboratory research setting for 1 week during the school holidays. A potential future scientific researcher was engaged with science more closely than usually possible. |
Year(s) Of Engagement Activity | 2010 |
Description | Undergraduate summer student |
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 | An undergraduate student from Brunel University reqested to spend time working in the lab to experience hands-on the workings of a research laboratory. A potential future scientific researcher was engaged with science more closely than usually possible. |
Year(s) Of Engagement Activity | 2009 |