Community Research and Development Information Service - CORDIS

Periodic Report Summary 2 - MITIGATE (Closed-loop Molecular Environment for Minimally Invasive Treatment of Patients with metastatic Gastrointestinal Stromal Tumours)

Project Context and Objectives:
Gastrointestinal stromal tumour (GIST) is a rare disease with an annual incidence of about 1.5/100,000 persons. GIST frequently affects young patients with high potential for metastasising, which often results in a short life expectancy of less than 3 years on average. Currently there is only one class of effective medications for systemic GIST therapy and often the tumours develop drug resistance after a few years. No molecular imaging technologies indicating drug resistance, early therapeutic response or disease progression are clinically available. Furthermore, effective targeted agents with other mechanisms of action such as endoradiopharmaceuticals are not designed for treatment of GIST and alternative minimally-invasive treatment options for metastatic disease are not well explored nor has the clinical value of their combined use been established. The facts that GIST metastases frequently develop secondary mutations while being under imatinib or sunitinib treatment and consequently are no longer responsive to the drug demonstrates the urgent need for a new treatment strategy.
The overall objective of the MITIGATE project is to develop and validate an integrated closed-loop process to effectively treat metastatic GIST patients resistant to the currently available class of medication, the tyrosine kinase inhibitors (TKI). This personalised treatment concept combines innovative strategies for biopsy, inline tissue analysis, molecular tumour characterisation, theranostics by imaging technologies (PET and MRI) and companion radiopharmaceuticals followed by the assessment of biodistribution, dose calculation and measurement of therapeutic effectiveness.
The new treatment for GIST metastases can be used as a role model for other molecularly characterised cancer subtypes.
In detail, MITIGATE’s objectives are:
1) Optimisation of biopsy and tissue preparation in suspected GIST for integrated analysis and subtyping of molecular markers.
2) Provision of a large, characterised tumour bank of TKI-responsive and -resistant GIST, for generating novel pre-clinical models envisioned revealing novel markers for TKI-resistance.
3) Application of molecular imaging probes for specific GIST features indicating drug resistance, early therapeutic response or progression.
4) Development of effective targeted agents with other mechanisms of therapeutic action such as endoradiopharmaceuticals for treatment in patients.
5) Combine this therapeutic approach with alternative, minimally-invasive treatment options for a personalised treatment in the metastatic situation with fewer side effects.
6) Non-invasive monitoring of treatment effects in clinical routine.
The close collaboration experts in the fields of molecular oncology, biotechnology, chemistry, radiochemistry, medical radiation physics, magnetic resonance, computed tomography and positron emission tomography imaging, interventional radiology ensures that these developments are translated into an integrated, closed-loop treatment platform that induces a shift of paradigm for individually tailored therapy of patients with TKI-resistant disease with higher effectiveness and fewer therapeutic side effects.
With the completion of the third year of the project the consortium that is made up of partners from academia and industry has achieved significant results. In the last year MITIGATE efforts will focus on the translation of pre-clinical results into clinical practice. Among other things, evaluation of the results of the clinical trial, further development of new GIST-specific radiotracers and an assessment of new functional and metabolic MR imaging methods of GIST tumours are the key goals for the last year of the project.

Project Results:
Project management activities comprised the day-to-day management of the project, quality assurance, management of ethical issues and coordination of boards and committees. Main results of WP2 Dissemination and Exploitation are the regular update of the MITIGATE website, the launch of two newsletters, the elaboration of dissemination material for patients and interaction with patient advocacy groups. Furthermore, the intermediate exploitation plan was prepared and steps towards the final exploitation plan were made. In WP3 Biopsy and Preparation for Molecular Analysis an endoscopic biopsy system was developed and validated. A negative selection was applied to enrich the specific tumour cells from the single cell solution. Results show that cells can be distinguished by their magnetic charge in a microfluidic device. Potential relevant masses for a classification of different tumour samples were identified and a standard procedure for preprocessing the MALDI MS spectrometry data was developed. A database for managing MS fingerprinting data was designed, acquired and installed. WP4 Target Analysis and Molecular Probe Design evaluated the classification of GIST tumours based on MALDI-ToF MS imaging technology on animal models and tested MALDI-ToF MS imaging of the distribution of the unlabelled targeting vectors NeoBOMB1 and fluoronorimatinib. Radiolabelling protocols for Fluoronorimatinib, 4 DOTA derivatized GLP-2 receptor ligands and a VEGF-analogue were established. A DOG-1 small molecule precursor and two more GLP-2 derivatives were synthesised. The native DOG-1 antibody was evaluated towards binding property using flow cytometry analysis. Several radiotracers showed promising results in vitro. A detailed physiologically based pharmacokinetic model was developed. Main results obtained in WP5 Preclinical Theranostics are the in vitro and in vivo characterisation of a new radiopharmaceutical with a theranostic potential in GIST patients. This radiotracer is the GRPR-antagonist bombesin analogue, NeoBOMB1, which can be labelled with both diagnostic and therapeutic radioisotopes. The NeoBOMB1 showed high affinity to the GRPR in vitro, as well as excellent imaging performance in GIST-bearing mice. Activities of WP6 Translational Studies were focused on the preparation and launch of the clinical trial. Regulatory and administrative work as well as planning of the patient’s recruitment was performed and the collaboration with patient advocacy groups was intensified. A clinical trial design was developed and requirements for physiologically based pharmacokinetic modelling were implemented. The trial was submitted to the Ethical Committee in May 2016 and a positive vote was issued August 5th 2016. The application was submitted to the Austrian Competent Authority and awaits approval. The study was filed to “”. A pilot batch and two GMP batches of NeoBOMB1 were tested implementing the preparation of 68Ga-NeoBOMB1 for the clinical trial. WP7 Minimally Invasive Therapy designed a concept to investigate different combinations of treatment that received a positive vote from the ethics committee. A strategy and tools to integrate the new markers for PET-CT imaging into the combination treatments were developed. Animal PET-CT was used to evaluate tumour volume definition based on the new tracer. In terms of development of an assisting device for minimally invasive treatments, the evaluation of the manipulator systems showed promising results in terms of precision and intervention time. In WP8 Multimodal Therapy Control a dedicated 23Na-MRI coil was produced, tested and first results in volunteers and in one GIST patient were obtained. At preclinical level, experiments following imatinib treatment were performed on different GIST cell lines and several imaging modalities have been exploited for assessing drug response. Based here on a clinically feasible functional MR imaging protocol including the 23Na-MRI coil was designed.

Potential Impact:
The highly complex research carried out within MITIGATE leads to a variety of project results and outputs. Each of these achievements will strongly impact GIST patients, improving their personalized diagnosis and treatment. MITIGATE findings may in many cases be transferable to other cancer types for even higher socio-economic impact. Our newly established GIST-biopsy process involves a novel endoscopic biopsy device, biological upstream processing systems, a bespoke immunomagnetic single cell separation procedure and innovative mass spectrometry approaches. It will ensure high-quality molecular analysis of the tumour samples. Through development and application of the GIST subtype database and dedicated GIST subtype tumour animal models, combined with the possibility to predict TKI-resistant GIST behaviours, personalised selection of an appropriate PET probe or endoradiotherapeutic tumour treatment will be achieved. The whole procedure will result in an accelerated decision making process for the treatment of individual patients. AAA has developed an SOP for the radiolabelling of peptides with 68Gallium using a proprietary kit approach that is successfully applied to the NeoBOMB1 peptide, the selected probe for the clinical trial. The establishment of 68Ga-NeoBOMB1 PET-CT for molecular phenotyping in GIST tumours enables AAA to develop a novel diagnostic approach for GIST patients. Potentially this knowledge can also be translated for studies on new GIST treatment agents. A dosimetry study will be performed on GIST patients receiving the diagnostic agent 68Ga-NeoBOMB1. Using the already established PBPK model, these results will also allow a prediction of the compound’s behaviour for individualized targeted therapy approaches. After a positive ethics committee vote, MUI and AAA are working towards the final approval of the first-in-human phase I/IIa study MITIGATE-NeoBOMB1 by the Austrian competent authority. Up to 12 patients currently or previously undergoing TKI-treatment, the majority with a first-line TKI resistance, will receive 68Ga-NeoBOMB1 in a two-part trial. The study aims to prove safety, tolerability, favorable pharmacokinetics and to define preliminary targeting properties. Furthermore, UHEI and Cage have synthesized a series of new GIST-specific radiotracers, which are currently under evaluation with the goal of optimizing diagnostic properties and assessing potential use in endoradiotherapeutic tumour treatment. Simultaneously, UHEI is investigating a radiolabelled imatinib derivative to evaluate the individual treatment response. Endoradiotherapeutic treatment will be supported by minimally-invasive interventions, i.e. percutaneous thermal and non-thermal tumour ablation and irradiation, guided by molecular PET imaging. Novel, PET-CT-based target volume definition for external beam radiotherapy based on 68Ga-NeoBOMB1 will be established. The high-risk areas within the tumour volume will be defined for an intensified treatment. The evaluation of the preliminary animal PET-CT data for EBRT therapy planning suggests that the new PET-tracer allows escalation of the dose to vital tumour cells, thereby further increasing tumour control probability and proves its significance for the minimally invasive interventions. Entirely non-invasive, molecular MRI techniques based on physiological 1H and23Na MRI in combination with quantitative DWI/DCE/CEST-MRI and DECT will allow earlier detection of devascularisation and cytotoxicity related to tumour response/progression in clinical routine follow-up procedures. DCE-MRI and DWI approaches can distinguish between imatinib-sensitive and -resistant GIST tumours, thus these techniques have the potential to serve as new biomarkers for classification of GIST patients exploiting differences in tumour vasculature and cellularity. Based hereon, a comprehensive MRI protocol has been set up for surveillance of GIST patients in clinical routine.

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