Abstract LB023: Design of a ligand targeted radiotherapy for treatment of bone metastasis

Abstract ∼400,000 cancer patients with bone metastasis are diagnosed each year in the USA (American Cancer Society data), with cancers of the breast, prostate, lung and plasma cells (multiple myeloma) contributing most prominently to this burden. Because bone metastases are frequently accompanied by skeleton-related events, including fractures, severe pain, and loss of mobility, they frequently reduce both quality of life and overall survival. Unfortunately, current treatments for bone metastases are largely palliative and can cause off-target toxicity due to their lack of specificity.To directly treat bone metastases, we have designed a hydroxyapatite-targeted radioligand therapy composed of an acidic oligopeptide ligand tethered to a DOTA-chelated therapeutic radionuclide (177Lu) via a stable linker. The desired bone cancer specificity is achieved because both osteolytic (e.g. breast cancers) and osteoblastic (e.g. prostate cancers) bone lesions expose hydroxyapatite that is normally occluded in healthy bone by a cartilaginous sheath. Dosimetry data (AUC) from mice bearing osteolytic breast cancer xenografts (4T1 cells) in their tibias confirm the selectivity of this acidic oligopeptide conjugate for bone metastases in that tumor to healthy tissue ratios (% injected dose/gram-hr for tumor/ % injected dose/gram-hr for healthy tissue) for blood (1912), heart (520), lungs (862), liver (468), spleen (409), kidneys (156), muscle (1006), and healthy bone marrow (159) all vastly exceed those required to halt tumor growth without causing off-target toxicity to healthy tissues. More importantly, a single 18.5 MBq dose (3 nmoles/mouse) is observed to suppress tumor growth by 75%, with no evidence of solid tissue toxicity and minimal indication of transient lymphocyte suppression. Because these dosimetry and safety data support the administration of multiple doses of radiotherapy, this radioligand therapy is now undergoing IND-enabling studies for clinical evaluation in the near future. Citation Format: Losha D. Jung, Neel T. Parekh, Nithin R. Raj, Lauren K. Thompson, Philip S. Low. Design of a ligand targeted radiotherapy for treatment of bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB023.