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P1: Substrate-like protease probes

Substrate-like inhibitory probes for radioimaging (PI Matthias Eder).

The emerging role of substrate-like inhibitory probes as theranostic radiopharmaceuticals is demonstrated by the high clinical impact of PET/CT imaging and targeted radiotherapy of prostate cancer using low-molecular weight protease inhibitors of GCP-II / PSMA. In particular, molecular imaging by PET (positron emission tomography) employing probes selective for cancer-associated proteases allows the non-invasive, holistic visualization of cancerous lesions and can directly inform on the choice of targeted therapy, staging, and real-time response during and after therapy. The concept results in an improved personalized patient stratification, therapy monitoring and clinical management of cancer patients. The aim of the current projects is to identify innovative concepts using novel peptide-based inhibitory probes for radioimaging of cancer.

ProtPath offers two topics for doctoral work on radiopharmaceuticals:

1)   Radioimaging of the cancer cell associated protease MT1-MMP

EderBild1The project elucidates the feasibility of imaging metastasis formation and tumor invasion by targeting cancer-associated proteases.

As MMPs are known to be involved in cleaving the extracellular matrix, thereby supporting ECM remodeling and EMT, they contribute to cancer invasion and metastasis.

The figure shows µPET imaging (A) and ex vivo tumor tissue analysis (B) of a radiolabelled MT1-MMP binding bicyclic peptide. The compound visualizes the tumor with high contrast. The aim of the project is the further evaluation of the potential of imaging metastasis formation and tumor invasion using appropriate cell lines and in vivo models.

2)   In vivo Imaging and functional characterization of the urokinase-plasminogen system

EderBild2The urokinase-plasminogen system, i.e. the serine protease urokinase plasminogen activator (uPA) and its receptor (uPAR), plays a key role in cancer-associated extracellular matrix remodelling.

Enhanced levels of uPA protease in the tumor microenvironment is directly correlated with cancer progression, metastasis, and poor clinical outcome.

Novel peptide-based molecules will be developed targeting the active uPA and the complex of active uPA and uPAR. The peptides will allow the profiling of several mammalian cell lines and tissue samples.  Tumor-associated inflammation will be studied by imaging uPA/uPAR expression in immuno-competent mice bearing 4T1 tumors with uPA/uPAR-knock-down.