Enhancing the therapeutic efficacy of peptide receptor radionuclide therapy for neuroendocrine tumors

Neuroendocrine tumors (NETs) are cancers that originate in hormone-producing cells in the endocrine system, and they can arise throughout the body. Despite exciting breakthroughs in peptide-based targeted radionuclide therapy for NETs with a beta-particle emitters (e.g., Lutathera), outcomes of the therapy are often disappointing, and complete remissions have rarely been achieved (<2%). Thus, there persists an urgent need to improve our approaches to NET treatments. One such approach is alpha-particle therapy. Alpha particles deposit highly-localized energy to tumor cells, while minimizing stray interactions with normal tissues surrounding the targeted tumors. In addition, because a cancer-cell-targeted peptide (as a delivery vehicle that carries the radiation to the tumor) plays a key role in the success of the targeted therapy, the development of an improved form of the peptide can potentially enhance the efficacy of the therapy (with lower toxicity), by improving the precision of delivery. Further, emerging evidence suggests that the efficacy of targeted-radionuclide therapy can be enhanced by combining the radiation therapy with drugs that increase the cell surface density of the target receptor (SSTR2 for NETs) and improve tumor growth inhibition. The present study evaluated ²¹²Pb, an attractive alpha-particle emitter, for use in the targeted therapy, and developed a new form of SSTR2- targeted peptide that substantially improved tumor targeting – with significantly reduced production of biomarkers indicative of normal organ toxicity. Finally, studies designed to investigate the potential of combining current FDA-approved drugs with targeted radionuclide therapy suggested a promising translational potential of the approach, for which further studies are warranted. Thus, this dissertation is anticipated to improve our understanding of the potential efficacy and toxicities of ²¹²Pb-based targeted therapy and contribute to enhanced approaches to the treatment of NETs.