A small animal radiation research and multi-spectral optoacoustic tomography facility for advancing the physics and engineering of novel radiotherapy

BACKGROUND
Radiotherapy (RT) is one of the most efficient tools in cancer treatment, and clinical RT is evolving considerably with technological advances in delivery and treatment planning. A key component of modern RT is enhanced image guidance, needed for precise tumour targeting, therapy monitoring and therapy assessment. To achieve the best care for patients with cancer receiving RT, developments are needed to optimise the physics and technology of image guidance. This should include the exploitation of new discoveries in targeted drugs and nanoparticles that increase tumour sensitivity to radiation, and of synergisms between RT and other physical therapies such as high intensity focused ultrasound (HIFU), hyperthermia and ultrasound (US) microbubble damage to tumour vasculature. These novel approaches to image guided RT must first be investigated in a preclinical setting before the most promising techniques can be translated to clinical studies. For this work, the integration of the best preclinical therapy with the best preclinical imaging will play a crucial role.

To replicate the sophistication of clinical radiation treatment methods for preclinical research requires significant technological advances to systems such as the small animal radiation research platform (SARRP), including the integration of reliable methods for image guidance. US imaging methods, including multispectral optoacoustic tomography (MSOT), offer the potential for improved and complementary image guidance capability relative to existing methods based on x-ray, nuclear medicine (NM) and magnetic resonance (MR) imaging.

RESEARCH
We aim to (a) develop an integrated SARRP-MSOT image guided preclinical RT facility and (b) use it to aid the development and optimisation of novel imaging methods and probes, and new therapeutic synergisms, to either evaluate or enhance effects of radiation on cancer cells. Over a five year period, 7 physics teams will conduct research in the following areas.

The SARRP will be modified for co-registration with MSOT and for preclinical tumour treatment using the most advanced methods employed clinically, under image guidance. We will develop methods for accurate determination of applied radiation dose and integrate a special x-ray detector for quantitative computed tomography able to distinguish tissue types and detect dose-enhancing nanoparticles.

We will investigate possibilities to exploit therapeutic synergisms by integrating US therapy with the SARRP. We will modify the MSOT device for US microbubble imaging, using MSOT imaging of blood supply and oxygenation to optimise RT and US treatment combinations, investigating the use of US microbubbles to enhance RT, and developing dose parameters for combined physical therapies.

Imaging techniques and probe chemistry will be developed and optimised for MSOT prediction of enhancement of targeted radiosensitisation, indication of prognosis and assessment of tumour response. Performance will be compared with NM probes and MR imaging techniques.

Methods for US guidance of advanced RT treatments will be optimised by developing co-registration of US images with NM, MR and MSOT images that predict radiosensitivity, and developing and evaluating US-based motion compensated dose delivery and imaging to identify the distribution of viable tumour cells as treatment progresses to facilitate treatment adaptation to avoid relapse.

Finally, cross-institutional collaborative research in the above and other areas will be fostered by making the integrated facility available to external users and by running workshops for sharing technical and scientific information, and planning, executing and reporting on joint studies.

The primary non-academic beneficiaries, in the longer term, will be cancer patients. Research and development with the MSOT system will provide sophisticated, novel, imaging techniques and imaging probes that will allow a better understanding of tumour behaviour and response to treatment. MSOT, with its high resolution, whole body 3D, real-time imaging of molecular and functional information, is the most suitable imaging tool for combining with the SARRP in the preclinical research described in this proposal. Because of its limited penetration depth, however, it will not always be the most suitable tool for clinical application. The research will therefore act to inform development for eventual translation to clinical application with chemical probes and image information either directly, as clinical optoacoustic imaging for appropriately superficial organs or those accessible by endoscopy, or indirectly, albeit at lower resolution, by using radiolabelled equivalent probes for nuclear medicine imaging or equivalent image biomarkers employing MRI. This is one of a number of reasons why the proposed research includes cross-modality image registration, image fusion and multiparametric image analysis. The SARRP will allow the pre-clinical testing of new image guided radiotherapy (RT) techniques whether on their own, or in combination with other treatment modalities, enabling their optimisation and comparison with established methods before they are implemented for the benefit of patients. Such implementation holds considerable potential for collaboration with industry. The pre-clinical research enabled by the use of these two pieces of equipment will lead to improved diagnosis, more effective RT treatments, and better treatment monitoring. Siting the devices at The Institute of Cancer Research will have obvious benefits. The tie up between the ICR and the Royal Marsden NHS Foundation Trust ensures rapid translation of new ideas into the clinic, the two organisations having an excellent track record of industry collaboration and commercialisation of inventions in both imaging and RT with companies such as Elekta, Philips, Seimens, and Zonare. The preferred MSOT provider, iThera, has an interest in clinical translation of the research findings and to assist with this has offered to contribute (see quotation) an open system with research access and a hand-held hemispherical array, with engineering support. The SARRP supplier, Xstrahl, has made equivalent undertakings to assist the research. Both suppliers also represent excellent routes for direct commercialisation in the preclinical research industry. The proposed implementation of IMRT and VMAT on the SARRP, will ensure the clinical relevance of the research and opportunities for rapid translation to the clinic. In modern RT the emphasis is on integration of diagnosis and therapy to provide treatments that are personalised for each patient. Users from outside the ICR, who will have access to this equipment, have similar goals. The development of patient specific biomarkers for disease, and of RT treatment plans that follow individual tumour contours more closely, and follow functional and molecular information that defines the biologically important target, are essential for this strategy. Investigation of these areas will be greatly enhanced by the use of the two devices requested. The users of the equipment will thus be excellently placed to ensure that this research is translated as rapidly as possible into the clinic, and thus for the benefit of the patient. More effective RT treatments, in terms of optimised dose delivery, sometimes achieved by combination with radiosensitisers or synergistic treatments, will result in fewer side effects, and thus improved tumour control and greater quality of life for patients. The improved treatment monitoring techniques that may result from this work, would allow earlier re-intervention in the case of treatment failure.