This doctoral research project has the overall aim to develop and validate radionuclide therapy for the treatment of metastatic melanoma (both primary tumour and metastatic lesions) by 188Re-labelled carrier molecules based on quantitative imaging and dosimetry. At the end of this project, we intent to have preclinically validated 188Re-labelled carrier molecules for theranostic treatment of melanoma.
Appropriate selective carrier molecules are essential in this story to target specific cancer cells. Several carriers have been developed, labelled with therapeutic isotopes 131I, 90Y, 177Lu and more recently alpha-emitters such as 213Bi, 211At and 225Ac in preclinical experiment and early phase clinical trials in melanoma (Raja, et al., 2007). Three categories of carrier molecules are possible to use:
- Monoclonal antibodies, or fragments, targeting at melanoma-associated antigens such as HMW MAA, 6D2 or GD3 (Klein, et al., 2013);
- Peptides such as MSH (melanocyte-stimulating hormone) analogues or melanin-binding decapeptide 4B4 (Miao, Owen, Fisher, Hoffmann, & Quinn, 2005);
- Small molecules binding to components intra- or extracellular, such as the melanin binding benzamide (MIP-1145, BA52) (Joyal, et al., 2010) (Mier, et al., 2014).
This project will focus on category 2 & 3 carrier molecules (peptides and small molecules).
The radiolabelling of the carrier molecules with 188Re will be performed using bifunctional chelating agents such as MAG3, HYNIC and DTPA that form stable complexes with 188Re (Liu, 2008) (Sugiura, 2014). Such chelating agents have the advantage that they can bind to metals, but also possess a chemically reactive functional group so they can be covalently bound to the carrier molecule. The stability of the 188Re-labelled carrier molecules will have to be assessed in vitro and in vivo. Finally, the imaging and therapeutic potential has to be demonstrated.
Project work packages (WPs) include:
- Optimization of radiochemical procedures for the labelling of the carrier molecule(s) by selection and validation of appropriate bifunctional chelating agents, selecting an appropriate perrhenate reduction method, and selecting the most suitable labelling approach. Readouts will be yield (overall yield and yield of the individual steps) and purity after labelling.
- Assessment of the radiochemical stability of 188Re-labelled carrier molecules in storage and physiological conditions.
- In vitro studies on tumour cell lines, with a clear view on specificity of binding, affinity, and degree of internalisation.
- Development of quantitative imaging methodology for 188Re. This includes phantom studies to determine energy window optimization, collimator choice and corrections for high energy contamination. Based on the images obtained with microSPECT, maps of dose distribution are determined with convolution based or Monte Carlo methods. This WP will also assess the feasibility of a model with the sole theranost 188Re versus the tandem 99mTc/188Re.
- In vivo studies in different human tumour xenografted mouse models for melanoma to assess the stability, biodistribution, tissue penetration and tumour targeting.
- In vivo toxicity studies (histopathology and analysis of functional parameters in serum or urine) based on the outcome of biodistribution studies (WP5).
- Therapeutic efficacy of 188Re-labelled carrier molecules in relevant preclinical cancer mouse models.
This research project will be conducted by the Radiochemistry group (RCA) of the Belgian Nuclear Research Centre (SCK•CEN) and the IMIT (Innovative Molecular Imaging and Therapy) consortium of the University of Gent (UGent). RCA will provide the 188Re isotope and develop stable 188Re-labelled carrier molecules. UGent will provide the carrier molecules and perform preclinical evaluation of the 188Re-labelled carrier molecules by in vitro and in vivo characterisation. In a later stage of the project, in vitro and in vivo characterisation could be complemented by analogous studies performed at SCK•CEN.
An important and major part of the work is centred around work packages 1&2 and will be carried out in the Radiochemistry expert group of SCK•CEN. The work related to the other work packages will be carried out in the first stage of the project in the IMIT consortium (Radiopharmacy, MEDISIP and Infinity lab and Nuclear Medicine groups of UGent) and in a later stage of the project possibly at SCK•CEN.
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Klein, M., Lotem, M., Peretz, T., Zwas, S., Mizrachi, S., Liberman, Y., et al. (2013). Safety and Efficacy of 188-Rhenium-Labeled Antibody to Melanin in Patients with Metastatic Melanoma. Journal of Skin Cancer, 2013, 1-8.
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