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Straeter, N.

Publications and source records attributed to Straeter, N..

2 recordsLinked to original sources
bioRxiv2024

Positron emission tomography (PET) tracer enables imaging of high CD73 expression in cancer

Ecto-5-nucleotidase (CD73) is a potential new drug target for cancer immunotherapy. Its overexpression is associated with various aggressive cancers, including triple-negative breast cancer (TNBC) and pancreatic cancer, making it a promising target for diagnostic imaging. Besides antibodies, small molecule CD73 inhibitors have been developed and are currently in clinical trials. This study aimed to develop and evaluate fluorine-18 labeled high-affinity CD73 inhibitors as tracers for the non-invasive positron emission tomography (PET) imaging of CD73 expression in cancer. Two CD73 inhibitors were selected for radiolabeling based on their high potency (Ki values of ca. 1 nM), and favorable pharmacokinetic properties providing [18F]PSB-19427 ([18F]1) and [18F]MRS-4648 ([18F]2). Ex vivo imaging studies on human breast cancer tissues indicated specific binding of both radiotracers. Subsequent in vivo studies proved [18F]1 to be superior due to its long elimination half-life and its accumulation in TNBC and pancreatic cancer tissues, suggesting its potential as a versatile PET tracer for imaging various solid tumors. [18F]1 significantly outperformed [18F]FDG in visualizing triple-negative breast cancer, offering potential advantages over [18F]FDG in terms of specificity and diagnostic accuracy. Thus, [18F]1 is a PET tracer with outstanding properties suitable for broad application in cancer diagnosis and potentially in therapy control. Based on these results, further clinical development of PET tracers targeting CD73 is warranted. One Sentence SummaryA PET tracer for imaging CD73 expression was developed, enabling cancer diagnosis.

cancer biology↗
bioRxiv2022

PTK7 is a positive allosteric modulator of GPR133 (ADGRD1) signaling in GBM

GPR133 (ADGRD1), an adhesion G protein-coupled receptor, supports growth of glioblastoma, a brain malignancy. We demonstrated that GPR133 is intramolecularly cleaved, and that dissociation of its N-terminal and C-terminal fragments (NTF and CTF) at the plasma membrane correlates with increased receptor signaling. However, how the extracellular interactome of GPR133 in glioblastoma modulates signaling remains unknown. Here, we use affinity purification and mass spectrometry to identify extracellular binding partners of GPR133 in patient-derived glioblastoma cells. We show that the transmembrane protein PTK7 binds the GPR133 NTF and its expression in trans increases GPR133 signaling. This effect requires the intramolecular cleavage of GPR133 and PTK7s anchoring in the plasma membrane. The GPR133-PTK7 interaction facilitates orthosteric activation of GPR133 by soluble peptide mimicking the endogenous tethered Stachel agonist, suggesting PTK7 binding allosterically enhances accessibility of GPR133s orthosteric Stachel binding pocket. GPR133 and PTK7 are expressed in adjacent cells in glioblastoma, where their knockdown phenocopies each other. We propose that this novel ligand-receptor interaction is relevant to the pathogenesis of glioblastoma, as well as physiological processes in several tissues.

cell biology↗