MITIGATE · Closed-loop Molecular Environment for Minimally Invasive Treatment of Patients with metastatic Gastrointestinal Stromal Tumours

Gastrointestinal stromal tumours (GIST) are a rare disease that metastasises in up to 85% of patients with subsequent median progression-free survival (PFS) of only around 30 months. Tumours are characterised by activating mutations in the KIT or the PDGFRA gene and therefore treatment is mainly based on tyrosine kinase inhibitors designed to block these mutated receptors. However, drug resistance is often based on mutations changing the conformity of the receptor, leaving little effective therapeutic options to these patients. To date, second line chemotherapy offers a median PFS of 6-9 months and external beam radiotherapy is limited by organs at risk close to the tumour. Alternative approaches such as endoradiotherapy or minimally-invasive ablation techniques are effective for local control but are inconsistently used and are not tailored to the individual patient's type of disease. To address these issues, we propose a closed-loop personalised treatment concept combining endoscopic-assisted tissue sampling, inline biotechnology and targeted molecular PET imaging probe development combined with minimally-invasive treatment monitored by new functional and metabolic MR imaging techniques. A consistent value chain across European academic centres, research institutes and SMEs will be established for mass spectrometry of tumours, linkage of radiochemical molecular imaging probes, design of new immunocompromised animal models and targeted therapeutic radiopharmaceuticals. This closed-loop platform will minimise fragmentation of treatment approaches by a coherent molecular-based multimodality concept, thus providing new treatment options. On a larger scale, the MITIGATE platform can be expanded to further patient cohorts with oligometastatic diseases such as other sarcomas or renal cell carcinoma. For SMEs the access to new animal models and ligands along with translation into clinical practice will strengthen their market share for new probes and imaging technology.