Assessing the potential of radiolabeled bacterial signal peptides as useful tools for basic research and diagnostic tumor imaging

• Applicants: Dr. Mark Bartholomä; Professor Dr. Bernd Bufe
• Subject Area: Pharmacy ; Radiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537709933

Target-specific radiopharmaceuticals for molecular imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) help to provide precise information about the presence and expression level of tumor markers in individual patients, thus allowing a better patient staging and selection, more effective personalized therapy and an improved therapy monitoring. In this application, we propose to assess the potential of radiolabeled bacterial signal peptide derivatives as diagnostic and therapeutic tools for basic research, tumor imaging, and cancer therapy. Bacterial signaling peptides are high affinity ligands for formyl peptide receptors (FPRs) that are expressed at the cell surface of a number of cancer tissues. FPRs comprise a small family of G- protein coupled receptors that are a promising but yet mostly unexplored target for molecular imaging and radiotherapy. Their expression is upregulated in several especially malignant types of cancer such as glioblastoma multiforme, triple negative breast cancer, bladder cancer, ovarian cancer, pancreatic cancer and hepatic cancer. Of note, the upregulation of FPR expression is clearly associated with a higher malignancy of several tumor types. For example, high FPR1 expression in progressive primary human colorectal cancer is associated with poor patient prognosis, while a strong FPR1 expression in gastric carcinoma is associated with more advanced tumor stage and poorer overall survival of gastric cancer patients. They furthermore promote the malignance of glioblastoma multiforme and play a pivotal role in tumor cell growth, invasion and production of angiogenic factors. Thus, development of radioligands for FPRs can provide important tools for the diagnosis and treatment of especially malignant cancer types. We recently identified several new bacterial signal peptides that activate individual FPRs in picomolar concentrations, which makes them ideal candidates for the development of radioligands. We therefore propose to use these bacterial signaling peptides as templates for the design of effective receptor subtype-specific radioligands and to investigate their application for tumor diagnosis and peptide receptor-mediated radionuclide therapy of tumors with endogenous FPR expression. Of note, high affinity FPR-subtype specific radiotracers would be also of interest to investigate multiple other aspects of formyl peptide receptor biology. For example, they would be helpful to monitor receptor ligand interactions, receptor specific permeability of body barriers for the uptake of formyl-peptides and alterations in the tissue distribution of the formyl peptide receptor subtypes in different pathological conditions.

• DFG Programme: Research Grants