Radionukleär molekylär imaging av prostata cancer: gradering och fenotypning av tumörer för en individanpassad behandling
Tidsperiod: 2016-01-01 till 2019-12-31
Projektledare: Anna Orlova
Medarbetare: Stefan Ståhl, Vladimir Tolmachev, Mats Larhed
Budget: 4 000 000 SEK
There is an unmet clinical need to improve both diagnostics (especially detection of soft-tissue metastases) and therapy of prostate cancer (PCa). One possible approach is radionuclide targeting of receptors and antigens closely associated with disease progression (e.g. prostate-specific membrane antigen (PSMA), gastrin-releasing peptide receptor (GRPR), angiotensin AT2 receptor (AT2R), chemokine receptor 7 (CXCR7), and members of receptor tyrosine kinase (RTK) family, EGFR, HER2, HER3, IGF-1R). I propose to use radionuclide-based imaging for diagnostic, both staging and therapy selection, and therapy of disseminated PCa. Particularly: to use short synthetic bispecific peptides targeting simultaneously PSMA and GRPR for imaging and therapy of PCa metastases; to use radiolabeled non-peptide AT2R imaging probes for identification of PCa patients that could benefit from AT2R- targeting therapy; to use CXCR7-targeting imaging for detection of aggressive PCa; to use affibody-based probes for imaging of RTK overexpression of in PCa for selection of RTK-targeted therapy. I aim to test hypotheses that bispecific radionuclide molecular imaging agent, targeting both PSMA and GRPR, could (a) improve staging of the disease due to specificity to receptors overexpressed both in earlier and later stage of the PCa and (b) could be a therapeutic option for disseminated castration-resistant PCa; to introduce PET imaging probes for possible prognostic and predictive biomarkers in PCa, i.e. AT2R and CXCR7; to investigate biological factors influencing imaging contrast of RTK expression for the targets with endogenous expression in normal tissues (e.g. HER3 and HER1). Successful accomplishment of this research program will provide a number of imaging agents for visualisation of molecular targets in PCa including disseminated androgen-independent PCa. This would provide important predictive information for selection of appropriate therapy. Visualisation of therapeutic targets would not only serve for patient stratification, but also could be used for monitoring of therapy response. These will make PCa treatment more personalized. Furthermore, clinical imaging using radiolabeled GRPR/PSMA-targeting conjugates may increase detection sensitivity of PCa soft tissue metastases. A non-curative surgery might be avoided. Radionuclide therapy of PCa using radioiodinated GRPR/PSMA-targeting conjugate may be a more precise alternative to currently used external irradiation that will spare healthy tissue.