Enhancing the therapeutic efficacy of peptide receptor radionuclide therapy for neuroendocrine tumors
Creators: name: Lee, Dongyoul
Publisher: name: University of Iowa
Year: 2020
Subjects: Alpha-particle therapy
Neuroendocrine tumors
Pb-203/Pb-212
PRRT
SSTR2-targeted therapy
Theranostics
Toxicology

description: Neuroendocrine tumors (NETs) are heterogeneous neoplasms, which can arise in any location of the body. Although disease progression can be variable, NETs often progress relatively slowly and can be asymptomatic or accompanied by non-specific symptoms. Thus, NET patients often have inoperable tumors or metastases at the time of diagnosis of the disease, which requires effective systemic therapy. Somatostatin receptor subtype 2 (SSTR2)-targeted peptide receptor radionuclide therapy (PRRT) is a systemic therapy that has been known to be effective for the treatment of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, therapeutic outcomes with current beta-particle PRRT (i.e., Lu-177-DOTA0-Tyr3-octreotate; Lu-177-DOTATATE) for the treatment of GEP-NETs are largely limited to stable disease or partial response to the therapy (i.e., complete responses are rare). Emerging evidence suggests that alpha particle-based PRRT has the potential to enhance the efficacy of PRRT, and among the available radionuclides for this purpose, Pb-212 is an attractive alpha-particle emitter to use for therapy. In addition, emerging evidence suggests that the most commonly targeted receptor for drug delivery for NETs (i.e., SSTR2) can be pharmacologically upregulated in vitro and in vivo, suggesting the potential for improvement in tumor responses could be achieved when combined with PRRT.
description: The present studies investigated the relative merit of Pb-212 relative to other beta- and alpha-particle-emitting radionuclides in cells and tumor-metastases of various sizes using a computational modeling tool. In addition, laboratory investigations evaluated Pb-212-DOTA-Tyr3-Octreotide (Pb-212-DOTATOC) in terms of biodistribution, efficacy, and toxicity in a mouse model, showing the potential benefit and toxicities that would arise with the Pb-212-DOTATOC treatment of SSTR2 positive NETs. Concerns regarding potential toxicities of Pb-212-DOTATOC led us to pursue a dosimetry-based personalized approach to NET therapy using Pb-212-DOTATOC and the feasibility of this approach was demonstrated in an animal model. These studies included an investigation of the potential for structural modifications to the DOTATOC chelator-modified peptide that revealed new peptide structures (specifically for Pb isotopes), which improved tumor targeting and reduced systemic toxicity. The new peptides were synthesized by replacing the chelator with a new chelator composition called Pb-specific chelator (PSC) and inserting polyethylene glycol (PEG) linkers. A comprehensive evaluation of the peptide variants identified a promising structure for the Pb isotopes (referred to as PSC-PEG2-TOC). The peptide significantly improved tumor uptake and reduced normal organ retention relative to DOTATOC, which significantly increased the therapeutic index of the new radiopharmaceutical compared to DOTATOC. Finally, these studies investigated the potential of combining an inhibitor of the serine-threonine kinase mammalian target of rapamycin (everolimus, AFINITOR; an FDA-approved drug for NETs) and histone deacetylase inhibitors (HDACi) to improve the therapeutic outcomes of PRRT. Our in vitro data suggested that the combination of these drugs with Pb-212 PRRT induced an anti-proliferative effect at clinically-relevant concentrations – and also significantly upregulated SSTR2 in NET cells, suggesting a potential improvement in the therapeutic efficacy when combined with PRRT. However, in vivo biodistribution data was inconsistent with the in vitro data in terms of SSTR2 upregulation. Thus, these results suggest that more studies on dosing strategies should be performed to realize the potential for improved outcomes. Taken together, this work demonstrates in preclinical models that Pb-212-based PRRT has the potential to provide a safe and effective treatment for NETs and that structural modifications to peptide-based ligands for this purpose can be made that improve outcomes. It was further demonstrated that combining pharmacological drugs with PRRT has the potential to further improve outcomes. Thus, the results of this dissertation are anticipated to provide a platform that can significantly improve the translational potential of alpha-particle based PRRT for NET patients.