Emerging innovations in theranostics for pancreatic neuroendocrine tumors

Abstract

Pancreatic neuroendocrine tumors (pNETs) often overexpress somatostatin receptor type 2 (SSTR2), making them ideal targets for theranostics, which integrates molecular imaging with targeted radionuclide therapy. ¹⁷⁷Lu-DOTATATE significantly extends progression-free survival (22.8 vs. 8.5 months) compared to octreotide LAR. Despite these advances, challenges remain, including treatment resistance and long-term toxicities. In this review, we explore advancements in specialized imaging techniques, rationale combination strategies, and exploring next-generation radiopharmaceuticals.

Fig. 1. Radionuclide Detection and Treatment of pNETs.

This figure illustrates the radionuclide-based approach for detecting and treating pancreatic neuroendocrine tumors (pNETs). The process begins with the intravenous injection of ⁶⁸Ga-DOTATATE, a somatostatin receptor type 2 (SSTR2) agonist that binds to receptors expressed on the surface of neuroendocrine tumor (NET) cells. A subsequent PET/CT scan detects NETs by visualizing this receptor-ligand interaction. For treatment, patients receive ¹⁷⁷Lu-DOTATATE intravenously as part of peptide receptor radionuclide therapy (PRRT). The ¹⁷⁷Lu-DOTATATE binds specifically to SSTR2 receptors on neuroendocrine cancer cells, is internalized, and delivers targeted radiation directly to the tumor. This radiation induces DNA damage, leading to cancer cell death while sparing surrounding healthy tissues. Created in Biorender. Karimi, A. (2025).

Fig. 2. Beta and alpha radiation in targeted radionuclide therapy.

This figure illustrates the mechanisms of targeted radionuclide therapy via somatostatin receptor type 2 (SSTR2). The top pathway depicts beta radiation, which affects a broader area, targeting 10-100 cells and causing single-stranded DNA damage through the emission of electrons with a longer range. In contrast, the bottom pathway highlights alpha radiation, which impacts a much smaller area, targeting only 5-10 cells. Alpha particles deliver higher energy with a shorter range, resulting in highly localized and concentrated DNA damage, leading to irreparable double-strand breaks in tumor cells. Created in Biorender Karimi, A. (2025).