| Abstract: |
The birth of radionuclide therapy can properly be ascribed to Saul Hertz who initiated the experimental work that led to the development of radioiodine therapy in thyroid disease. This also paved the way for the development of novel thyroid diagnostics and ushered in new paradigms of radioisotope therapy. The latter included antigen-directed radioimmunotherapy and more recently, receptor targeted therapy (PRRT) directed at neuroendocrine tumors and more recently prostate cancer. This strategy was based upon radiation (typically 177Lutetium) coupled to peptides (either somatostatin analogs for NETs or PMSA for prostate cancer) that targeted specific receptors overexpressed by the tumor. The strategy of using isotopes both for diagnostic and therapeutic purpose has been denominated as theranostics. Although radionuclide therapies have efficacy, it has long been apparent that not all patients or tumors respond equally. Clinical features have only a limited ability to define efficacy or toxicity. Recent investigation has identified that factors intrinsic to the tumor and the host itself appear to determine the response to different treatments and the susceptibility to toxicity. The modulators of the responses to radionuclide therapy include diverse genomic regulators of biologic processes including metabolomics and the cancer determinants of proliferation, metastasis and immune response. Delineation of this diverse array of genomic regulators and their biologic pathway determinants have enabled identification of molecular biomarkers e.g., gene expression panels, that have utility as tools to determine a variety of clinical applications including patient stratification, the prediction of toxicity and the monitoring of disease. Previously such information was mostly obtained by clinical assessment or tissue analysis. The former strategy has limited application and the latter is invasive, cannot be undertaken repetitively and involves random sampling of heterogeneous tumors, thereby obviating its clinical utility. In recent times, the use of blood-based multi-genomic assessment, liquid biopsies e.g., NETest, PPQ, has provided molecular strategies effective in real-time, non-invasive evaluation of radionuclide therapy. Current investigation indicates that mapping the genomic and metabolic basis of radionuclide therapy remains a critical future objective to optimize, patient selection, predict therapeutic efficacy, assess outcome ad predict toxicity. Future refinements and advances of radionuclide therapy require the genomic delineation of the tumor and host to provide personalized therapy and optimize outcome. © 2022 Elsevier Inc. All rights reserved. |
