Challenges in Nuclear Medicine: Innovative Theranostic Tools for Personalized Medicine

Over the past few years, nuclear medicine has undergone impressive growth with the development of positron emission tomography (PET), especially using 18Ffluoro-deoxy-glucose (18FDG), and new approaches in targeted radionuclide therapy. These developments pave the way for personalized medicine by offering practical solutions, especially in oncology, neurology, and cardiology. Novel radiopharmaceuticals targeting relevant biomarkers are powerful patient selection tools for patients who may benefit from targeted therapies, and for early therapeutic response assessment. Moreover, once labeled with betaor alpha-emitters, radiopharmaceuticals targeting relevant molecular markers expressed by different solid tumors, and hemopathies can be used for radionuclide therapy. The final objective here is to eradicate residual cancer disease by using cytotoxic mechanisms complementary to those of “non-radioactive” therapies. PET imaging and targeted radionuclide therapy then come together in the context of the theranostic approach to adapt injected activity for personalized therapy. 18FDG–PET demonstrates the high accuracy and the clinical benefits of noninvasive whole-body imaging. It is used in clinical practice for initial staging and therapy evaluation in several solid tumors and hemopathies. 18FDG–PET is also applied outside oncology to explore dementia, assess myocardial viability, or detect infectious and inflammatory processes. However, 18FDG is not a specific tracer. For example, in solid tumor or lymphoma assessment, 18FDG–PET does not distinguish tumors from inflammation, inducing false positive results, especially after therapies inducing inflammatory or immune reactions. New radiopharmaceuticals are needed to better characterize pathologic processes and to predict and assess response to therapy (1). In oncology, the development of 18FDG–PET is ongoing, particularly for therapy response assessment. Image acquisition and analysis protocols are being further standardized to improve diagnostic accuracy (2). For example, specific criteria have been elaborated to assess lymphoma or solid tumor response to therapy (2–4). For tumors with low avidity for 18FDG, other 18F-labeled compounds are being proposed (e.g., 18F-choline in prostate cancer or hepatocellular carcinoma) (5). In addition, phenotype-specific tracers are needed for theranostic applications: 68Ga-labeled somatostatin analogues improve image quality in neuroendocrine tumors in comparison to 111In-octreotide available in clinical practice, with a significant clinical impact. Several 68Ga-labeled somatostatin analogues with variable performances have been evaluated (6–8). These novel imaging radiopharmaceuticals are particularly interesting because coldand radio-labeled somatostatin analogues are efficient for therapy of neuroendocrine tumors. Numerous peptides, targeting other receptors, are in development. Radiolabeled bombesin analogues show promise for prostate cancer (9, 10). Radiolabeled RDG peptides targeting the αvβ3 integrin have potential in a large spectrum of indications in the field of oncology but also in cardiovascular diseases (11, 12). Targeted therapies, including monoclonal antibodies (MAbs), experience a considerable growth in cancer management. MAbs are also promising vectors for theranostic approaches, to better identify patients who will respond and to monitor responses (13). Based on immuno-PET, treatment strategies could be tailored for individual patients before administering expensive and potentially toxic therapies. Until now, only invasive methods such as biopsy with immunohistochemistry analysis could identify patients who have the highest chance of response to antibodybased therapy. Immuno-PET can offer a non-invasive solution to quantitatively assess target expression. For example, antiHER2 therapeutic agents are most effective in patients who have HER2-positive breast cancer as determined by immunohistochemistry. It has been proven that MAbs labeled with 68Ga, 64Cu, or 89Zr could noninvasively identify lesions that are likely to respond to therapy (14–16). Immuno-PET is also a powerful innovation to improve knowledge about the efficacy and in vivo behavior of MAbs. Imaging plays an increasing role in the development of new drugs by pharmaceutical companies: in vivo imaging constitutes an effective solution for the rapid assessment of drug candidates, which may be radiolabeled to monitor their pharmacokinetics and biodistribution during preclinical and early clinical phases. Alternatively, molecular imaging using radiopharmaceuticals, combined with biomarkers, gives information about the quantitative variation of molecular targets during treatments. Indeed, if 18FDG–PET can be used (17), radiolabeled tyrosine kinase inhibitors (TKI) analogues are also developed to evaluate TKI efficacy in clinical trials by PET imaging (18). Nuclear medicine is also advancing cancer therapy. Clear examples are the treatment of non-Hodgkin’s lymphoma by antiCD20 or CD22 MAbs labeled with yttrium90 (19, 20) and of neuroendocrine tumors by somatostatin analogues labeled with