Molecular Imaging and therapy with radionuclides of prostate cancer

Abstract Prostate cancer (PC) is the most common type of cancer in men worldwide leading to substantial morbidity and mortality. At present, imaging of PC is indicated for primary diagnosis, staging and re-staging, as well as for the detection of (biochemical) recurrent disease. Currently, conventional imaging modalities, including ultrasound, bone scintigraphy, and computed tomography (CT) are used to detect primary and metastatic PC for staging and risk stratification. Despite significant efforts, conventional imaging of PC does not contribute to patient management and do not allow tumor-specific imaging. Radionuclide imaging techniques such as single-photon emission computed tomography(SPECT/CT) and positron emission tomography (PET)/CT provide both high sensitivity to detect tumor lesions, and characterization of the disease at the molecular level (molecular imaging). Choline radiolabeled with C-11 or F-18 is currently used as PET tracer for (re)staging of PC. Since choline is a key precursor in the biosynthesis of phosphatidylcholine, a major component of the cell membrane,increased levels of total choline incorporation have been observed in several malignancies. However, this molecular approach has limited sensitivity due to the lack of target specificity inherently to its uptake mechanism. The prostate-specific membrane antigen (PSMA) is a type II integral membrane glycoprotein that is selectively overexpressed in 90-100% of local PC lesions, as well as in cancerous lymph nodes, and bone metastases. Increased PSMA expression is correlated with an increase in tumor grade, pathological stage, aneuploidy, and biochemical recurrence. Most importantly, PSMA expression is upregulated when tumors become androgen-independent, showing elevated PSMA expression after anti-androgen therapy. This characteristic makes PSMA a reliable tissue marker for PC and is considered an ideal target for theranostic applications. Imaging probes specifically targeting PSMA are actively investigated and a number of highly promising agents radiolabeled with Tc-99m, F-18, Cu-64 and Ga-68 are currently under extensive clinical evaluation. Besides diagnostic imaging, radiolabeled PSMA ligands also have potential for radionuclide therapy of PC and a new therapeutic agent radiolabeled with Lu-177 has been developed and tested in patients.These promising preliminary clinical data encourage further studies to evaluate the potential for diagnosis and therapy (theranostic) of PC using PSMA ligands. The added value of this therapeutic regimen needs to be compared to conventional PC therapies. Recently, it has been surprisingly reported the observation of high and specific accumulation of copper ions in prostate cancer cells after administration of Cu-64 under the simple chemical form of dichloride salt. This result will open a new and unexpected route to PC diagnosis and treatment since the nuclear characteristics of Cu-64 allow using this radionuclide as both imaging and therapeutic agent. Clinical studies in patients are ongoing and showing high potential for this new approach. In this presentation, the clinical status of radiopharmaceuticals for theranostic applications in PC will be discussed