Community Research and Development Information Service - CORDIS

H2020

PRISAR Report Summary

Project ID: 644373
Funded under: H2020-EU.1.3.3.

Periodic Reporting for period 1 - PRISAR (Preclinical Intra-Operative Image-Guided Surgery and Post-Operative Radiotherapy of Tumours)

Reporting period: 2015-02-01 to 2017-01-31

Summary of the context and overall objectives of the project

Pancreatic cancer is a major cause of cancer-associated mortality, with a dismal overall prognosis that has remained unchanged for many decades. There are several factors that contribute to the poor prognosis of patients with pancreatic cancer. The most important point is that due to the lack of disease-associated symptoms, approximately 50-60% of the patients already have locally advanced or metastatic disease at the time of diagnosis. The median survival of patients with metastatic pancreatic cancer is 3 months.
Medical imaging has several important roles to personalize oncological management to the individual patient, ranging from initial diagnosis and staging towards early monitoring of therapy response and assessment of systemic control in metastatic patients. However, adequate visualization of the primary tumour and metastatic lesions using current imaging techniques and protocols is challenging in patients with pancreatic cancer. In a considerable number of patients, the primary tumour cannot be visualized.
PRISAR stands for Preclinical Intraoperative Image-Guided Surgery and Postoperative Radionuclide therapy of Tumours and in this context, intraoperative fluorescence imaging is a promising technique which potentially allows a better detection of tumor cells left at the resection margins. Fluorescence guided surgery is the first part of PRISAR and can already lead to an enormous improvement in survival rates. The challenge with pancreatic ductal adenocarcinoma (PDAC) are that they are often found near critical (vascular) structures which makes it difficult to remove them completely. Nowadays, the additional value of adjuvant therapies is very limited. With the use of targeted radionuclide therapy, for which the same target is used as for image guided surgery, via click chemistry, local treatment can be given. Since no tumor-targeting probes are yet available in clinical settings, the aim of the project so far was the evaluation of a cRGD peptide, targeting integrins overexpressed on the surface of tumor cells, as a potential tool for in vivo multispectral optoacoustic tomography (MSOT) and ex vivo fluorescence guided surgery. The main objective and basic concept of PRISAR is to improve intraoperative and postoperative targeted surgical probes and new detection systems for surgical intervention of cancer which can be specified by four keywords:
-Fluorescence & targeting - tumor visualisation during the operation for complete resection.
-Molecular radionuclidetherapy - postoperative targeted treatment.
-Standardisation - towards a gold standard.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In workpackage 1; is the development of a tumor margin specific fluorescent probe with a TCO tag for click chemistry. The first step was the development of the NIRF labelled contrast reagent and TCO tag with optimised affinity and selectivity for neovasculature structures, associated with carcinomas. Nowadays, cRGD-800CW-TCO is synthesized and validated both vitro, and ex vivo. The second step is to optimise a rapid bio-orthogonal reaction for targeted imaging and radiotherapy. In other words, the tumour-targeting (cRGD-800CW-TCO) construct will be conjugated to a small radiolabelled tetrazine probe.

In workpackage 2; the development of an optoacoustic camera system for open surgery. Nowadays it is proved that this can be used for imaging of human subjects in a range of clinical applications. Taken from the lab, the first prototype system was developed alongside a range of different handheld configurations that range in depth/resolution as models for various applications included intraoperative imaging. This led to the reiteration of the clinical concept, which took into account the experiences of the prototype and added in functions and features more relevant for use by clinicians. The system is currently in the process of being certified as a medical device for routine human use.

In workpackage 3; preclinical in vitro and in vivo validation of the probe developed in workpackage 1, the MSOT system in workpackage 2 and the other imaging modalities; Cellvisio, mass spectrometry imaging (MSI) and the small gamma camera.
For validation of the probe we developed and established a suitable, clinically relevant nude mouse model using orthotopic injection of human pancreatic tumor cell suspensions into the pancreas. This proved to be an important step in developing pancreatic tumor models that represent all steps of the metastatic cascade including local growth and vascular and lymphatic invasion at the local site. The AsPc1 model shows this cascade which makes this model highly suitable for the combination of image guided surgery and targeted radionuclide therapy.
For MSI, pilot experiments have been performed and optimization of protocols are underway. In those experiments both peptide and protein screening was performed. Evaluation of acquired MSI protein/peptide data will be analyzed to generate molecular images to identify tumour, non-tumour and tumour margin regions and the corresponding specific protein/peptide profiles.

In workpackage 4; targeted radionuclidetherapy by conjugating onto the probe, the additional value of targeted fluorescence guided surgery in combination with targeted radionuclide therapy should be proved. In the project we are heading towards workpackage 4 which means that we are already thinking about what types of IGS are performed in the clinic nowadays and how should we handle and analyse such big imaging data sets. Fortunately, within the PRISAR project, there is expertise regarding data dimensionality reduction approaches which can assist the interpretation of the data. The goal of this research will be to help clinicians to gain insight in how different pancreatic tumours are visualized on different imaging modalities and which information can be used to predict the biological behaviour of these tumours. Ultimately, this would contribute to the integration of imaging protocols in a multimodality imaging framework for personalizing the oncological management of patients with pancreatic cancers.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The project will build upon the current SME expertise available in Europe where such relationships are easier to bridge and where access to academic insight and collaboration is less fraught with difficulties. By empowering people with the knowledge of cross-sector issues and the multidisciplinary requirements of imaging, a new foundation of understanding will be achieved. This will help to build a more competent and employable European molecular imaging work force – ready for the next era of molecular imaging. At the start of this project we already acknowledged the fact that this project had the potential to produce the much-needed multi-disciplinary young professionals by active transfer of knowledge across different disciplines, as well as across an academic-industrial axis. After two years into the project, we can say that there is a high level of interaction and transfer of knowledge between several partners and secondees, partners with different backgrounds can help each other further. For this the highly wanted helicopter view is developed for a truly multi-disciplinary approach. Furthermore, the processing of big data as mentioned under workpackage 4 in the previous section, was not mentioned in the proposal but is additional progress beyond the state of the art which is highly likely to be be used in a broad range of diseases and not only cancer.
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