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

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Witney TH (2012) Evaluation of deuterated 18F- and 11C-labeled choline analogs for cancer detection by positron emission tomography. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Veronese M (2014) Parametric imaging of ¹8F-fluoro-3-deoxy-3-L-fluorothymidine PET data to investigate tumour heterogeneity. in European journal of nuclear medicine and molecular imaging

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Tomasi G (2011) Quantification of receptor-ligand binding with [¹8F]fluciclatide in metastatic breast cancer patients. in European journal of nuclear medicine and molecular imaging

 
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