Abstract Introduction: Recent literature demonstrates that the CGRPR, and its primary ligand, calcitonin gene-related peptide (CGRP) are implicated in 9 of the 14 hallmarks of cancer and contribute to the development of multiple primary cancers. Here, we developed a theranostic strategy for the SPECT imaging and targeted radiotherapy of CGRPR-positive tumors. Methods: The CGRPR-specific bioconjugate DOTA-Bn-NCS-FV-Tic-TDVGPFAF (ACP) was radiolabelled with 111In (SPECT: t1/2 = 2.8 d; Ee-max = 0.245 MeV) or 177Lu (β - emitter: t1/2 = 6.7d; E β-max = 0.497 MeV). Biodistribution studies in CGRPR+ HTB-10 tumor-bearing mice were conducted using 111InIn-ACP and radioactivity in tissue was quantified against a known radioactivity standard. Therapy studies with 177LuLu-ACP in the same tumor bearing model were also completed. As animals reached clinical endpoints, the animals were euthanized and processed for histology. QuPath software was used to quantify immunohistochemistry images, while survival and statistical analysis was accomplished using GraphPad Prism v.10.2. Results: The acute biodistribution of 111InIn-ACP revealed rapid excretion from blood, liver, kidney and bone suggesting effective clearance that may lead to acceptable dosimetry in dose-limiting organs such as the kidney and bone marrow. A tumor-to-muscle ratio of 39 at 4 h p.i., which was reduced to 12 with peptide blockade suggests that the radiopharmaceutical interacts with the CGRPR through a receptor mediated mechanism. Radiotherapy studies revealed that CGRPR+ HTB-10 tumor bearing mice injected with 177LuLu-ACP experienced a survival benefit when compared to animals receiving control treatments (p = 0.036). When analysed histologically, tumor sections from animals receiving the radiotherapy exhibited decreased Ki-67 staining (proliferation marker) but higher caspase-3 (apoptosis marker) staining when compared to tumor sections of untreated animals. Conclusion: Although the CGRPR/CGRP axis is implicated in cancer development, no theranostic strategies exist currently that target this receptor for imaging and therapy. Available data with 111InIn-ACP revealed effective tumor targeting and rapid clearance from normal tissues, while radiotherapy studies with 177LuLu-ACP demonstrated effective tumor growth control. These results suggest targeting the CGRPR/CGRP axis warrants further exploration as a promising new strategy for the imaging and therapy of cancer. Citation Format: Prabhakar Eeka, Darpan N. Pandya, Andrew F. Russo, Yusuke Shiozawa, Thaddeus J. Wadas. Theranostics targeting the calcitonin gene-related peptide receptor (CGRPR) demonstrate efficacy in a preclinical mouse model of human cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7188.
Eeka et al. (Fri,) studied this question.