Peptide receptor radionuclide therapy Research Papers (original) (raw)
A series of radiolabeled peptides have been designed and optimized for tumor-targeted peptide receptor radionuclide therapy (PRRT). Pre-clinical and clinical applications of PRRT have shown promising results on tumor response, overall... more
A series of radiolabeled peptides have been designed and optimized for tumor-targeted peptide receptor radionuclide therapy (PRRT). Pre-clinical and clinical applications of PRRT have shown promising results on tumor response, overall survival, and quality of life in patients with several kinds of tumors. 90Y-DOTA-TOC and 177Lu-DOTA-TATE are two of the most common radiopharmaceuticals with symptomatic improvements and complete clinical data. In addition to somatostatin analogs, radiolabeled peptides have been developed to target the relative receptors overexpressed in the tumors, such as integrin α vβ 3, gastrin-releasing peptide receptor (GRPR), melanocortin-1 receptor (MC1-R), cholecystokinin (CCK) receptor, and glucagon-like peptide-1 receptor (GLP-1R). Several strategies have been designed to improve the therapeutic efficacy of PRRT. For instance, radiolabeled peptides could be optimized by the amino acid modification and radionuclide selection. Healthy tissue protective agents and multi-cycle procedures could effectively decrease the side effects of PRRT. Furthermore, combination treatments, including PRRT combined with surgery, chemotherapeutic agents, or radiosensitizing agents could be applied to increase the effectiveness of PRRT. In this review, the current progress of peptide-based radiopharmaceuticals for tumor-targeted PRRT was summarized. Radiopharmaceuticals currently under clinical investigation were also described.
Patients with neuroendocrine tumors (NETs) often have metastatic spread at the time of diagnosis. NETs frequently express somatostatin receptors (SSTR) that can be targeted by radiolabeled somatostatin analogs (e.g. 177Lu-octreotate).... more
Patients with neuroendocrine tumors (NETs) often have metastatic spread at the time of diagnosis. NETs frequently express somatostatin receptors (SSTR) that can be targeted by radiolabeled somatostatin analogs (e.g. 177Lu-octreotate). Despite being highly effective in animal models (e.g. the human small intestine NET GOT1 transplanted to nude mice), 177Lu-octreotate-based therapies have shown low cure rates in clinical studies. The cellular processes that underlie positive treatment response to 177Lu-octreotate are largely unknown.
The aim of this work was to study the possibilities to optimize the therapeutic effects of 177Lu-octreotate in the GOT1 model in nude mice.
A literature study of available data on radiolabeled somatostatin analogs on NETs in animal models was performed, to identify strategies for treatment optimization. To test these strategies, GOT1-bearing BALB/c nude mice were treated with non-curative amounts of 177Lu-octreotate in different treatment schedules including single administrations, priming (fractionated) administrations and combination treatment with hedgehog inhibitor sonidegib. Biodistribution and dosimetry studies were performed and anti-tumor effects were monitored by measuring tumor volume. Global transcriptional and proteomic responses in tumor samples were evaluated using RNA microarray and liquid chromatography mass spectrometry, respectively.
177Lu-octreotate therapy of GOT1 tumors xenotransplanted in nude mice resulted in tumor volume reduction. Priming administration resulted in increased anti-tumor effects and increased therapeutic window. Combination therapy using sonidegib and 177Lu-octreotate resulted in prolonged time to progression. The global transcriptional and proteomic analyses of 177Lu-octreotate treated tumor samples revealed time-specific responses in terms of affected biological functions.
In conclusion, time-dependent changes in p53-related cell cycle regulation and apoptosis, angiogenesis, endoplasmic reticulum stress, and oxidative stress-related processes suggest possible niches for combination therapy at different time-points after radionuclide therapy. Priming 177Lu-octreotate therapy and combination therapy using sonidegib and 177Lu-octreotate could be beneficial to patients with NE-tumors.