Abstract 5735: Design of a peptide-targeted radiotherapy for treatment of bone cancers

Abstract According to the American Cancer Society, ∼400, 000 new cases of malignant bone metastases are diagnosed each year in the United States, with prostate and breast cancers accounting for the largest fractions. Unfortunately, progression of these metastases can lead to bone fractures, spinal cord compressions, hypercalcemia, and severe pain, resulting in a decrement in quality and duration of life. Given the limited effectiveness of existing clinical interventions in alleviating these symptoms, there is a critical need for therapies capable of selectively eradicating bone metastases without harming healthy tissues. To address this problem, we have developed a novel bone cancer-targeted radiotherapy comprised of an acidic oligopeptide that homes specifically to exposed hydroxyapatites (i.e. the mineral component of bone that becomes exposed in bone metastases) linked to a universal chelating agent (e.g. DOTA) that can bind to various cytotoxic radionuclides such as 177Lu, 225Ac, or 90Y. Tail vein administration of the 177Lu-labeled form of the above conjugate into nu/nu mice bearing intratibial C4-2 human prostate cancer revealed pronounced accumulation and retention of the conjugates in the tumor-induced bone lesions, with associated radioactivity decreasing modestly from 38% to 23% injected dose per gram (ID/g) from 4 hours to 240 hours. As the uptake in healthy tissues, aside from the kidneys, was minimal, and renal accumulation declined significantly from 2.8% to 0.13% ID/g over the same 240-hour period, it was concluded that bone metastases could be effectively irradiated without inducing measurable toxicity to healthy tissues. Subsequent therapeutic efficacy studies validated this prediction, demonstrating that serum PSA levels, a biomarker of C4-2 tumor growth, were significantly reduced in mice treated with the targeted radiotherapy, whereas untreated mice experienced disease progression necessitating euthanasia. Comparison of microCT scans between treated and untreated cohorts revealed a substantial reduction in bone lesions in the treated groups. Additionally, pathological examinations showed no detectable harm to kidney, blood, and bone marrow. These findings conclusively suggest that our bone cancer-targeted radiotherapy has the potential to improve survival and quality of life in this challenging patient population while minimizing toxicity. Citation Format: Losha D. Jung, Philip S. Low. Design of a peptide-targeted radiotherapy for treatment of bone cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5735.