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Molecular imaging of HER2 expression of breast carcinoma with radiolabeled Nanobodies (FWOAL499)

Aims of the research project Within the framework of this project we aim to develop a new targeting probe for molecular imaging of HER2 expression in breast cancer patients. For this purpose we will design a Nanobody with nanomolar affinity for HER2 that shows a fast blood clearance and low liver accumulation in vivo. Introduction: Malignant tumors are characterized by the presence of specific proteins on their cell membrane. These cancer antigens are expressed in relatively high amounts and often their expression level is related to a signal transduction cascade that contributes or promotes the cancer phenotype. Hence, these membrane antigens represent an important target for anti-cancer treatment. The human epidermal growth factor receptor type 2 (HER2) is a typical example of a membrane receptor that is highly expressed on the cell membrane of breast and ovarian carcinoma. Signaling of this receptor causes cell proliferation, enhances cell mobility and reduces apoptosis. Consequently, HER2 overexpression is associated with tumor aggressiveness and an increased probability for recurrent disease 1. Targeted therapies for HER2 overexpressing tumors are currently available, such as monoclonal antibodies (trastuzumab and pertuzumab) that specifically bind the extracellular domain of HER2, and specific tyrosine kinase inhibitors (lapatinib) that interact with the intracellular domain of HER2. Information on the HER2 status of tumors is therefore of great importance since it has an enormous impact on the selection of the patients' therapy. Nowadays, HER2 expression is assessed using tissue biopsies. In this project, we anticipate to develop a non-invasive evaluation of HER2 expression for breast cancer patients by means of imaging. This technique offers the advantage that the entire tumor lesion as well as possible metastatic lesions can be evaluated with a single scanning procedure. Additionally, 'sampling errors' with biopsies are avoided and the procedure can be repeated multiple times so that HER2 overexpression can be monitored during the disease process. This allows to select patients that are susceptible to a targeted therapy and to monitor the therapy response. Non-invasive imaging of HER2 expression has been studied by other research teams using different types of radiolabeled molecules that show affinity for HER2 (monoclonal antibodies, antibody fragments, affibodies, etc) 11-13. In most cases it was demonstrated that these diagnostic agents have the ability to bind HER2, both in vitro and in vivo. The most significant drawback of these tracers however, is the high background activity that is observed in the body. The bio-distribution often shows high tracer concentrations in the blood, intense accumulation in the liver or excretion through the gastro-intestinal tract. Such a background activity is suboptimal for the imaging process and limits the clinical use of these tracers. For that reason, in this project we will focus on the design of a new tracer molecule with an optimal in vivo bio-distribution. This is perfectly feasible by using Nanobodies. The generation of Nanobodies against a new antigen provides multiple candidates that are considered for further development. At this stage we will not only select the 'lead compound' as the one with the best target affinity, but we will also make a selection of Nanobodies based on the amino acid sequence of their backbone and their in vivo bio-distribution pattern.
Date:1 Jan 2009  →  31 Dec 2010
Keywords:image processing techniques, SPECT, image modelling and medical science, PET, small animal imaging, radiopharmaceuticals
Disciplines:Physical sciences, Electrical and electronic engineering, Basic sciences, (Bio)medical engineering