Innovative Radiotheranostic Strategy Targets Aggressive Cancers

Researchers at UCLA, in collaboration with international teams, have developed a promising new treatment approach to detect, target, and modify aggressive and treatment-resistant tumors such as osteosarcomas and glioblastomas. This novel method employs an engineered antibody, DUNP19, designed to target the LRRC15 protein found on the surface of certain cancer cells and their supportive stromal components. By attaching radioactive particles to this antibody, scientists can both visualize tumors with high precision and deliver potent radiation directly to cancer tissue, sparing healthy cells.

The study, published in Signal Transduction and Targeted Therapy, shows that in mouse models, LRRC15-guided radionuclide therapy effectively slows tumor growth, prolongs survival, and remodels the tumor microenvironment to enhance immune response. The antibody’s ability to deliver radioactive isotopes, such as Lutetium-177, acts like a guided missile, inflicting lethal damage to tumor cells expressing LRRC15. This approach also diminishes regulatory stromal cells that contribute to the tumor’s resistance to treatments like immunotherapy.

This 'radiotheranostic' technique offers dual benefits: it facilitates precise tumor imaging and provides a tailored, controllable radiation dose—mild for detection, intense for eradication—reducing side effects compared to traditional therapies. It is particularly effective against cancers like osteosarcoma, the most common bone cancer, and glioblastoma, a highly resistant brain tumor.

LRRC15 expression is stimulated by TGFβ, a growth factor that promotes tumor progression and immune evasion, but is scarce in healthy tissues. This makes LRRC15 an ideal target for selective therapy. The therapeutic antibody DUNP19 binds to LRRC15 and is rapidly absorbed by tumor cells, delivering lethal radiation directly to the tumor environment.

In preclinical studies, DUNP19 combined with radioactive particles demonstrated remarkable efficacy across various cancers in mice, including osteosarcoma, glioblastoma, triple-negative breast cancer, and colorectal cancer. The treatment not only shrank tumors and improved survival but also reprogrammed the tumor microenvironment, fostering immune cell infiltration and enhancing the effectiveness of additional immunotherapies.

The findings suggest this innovative approach holds significant potential to overcome the limitations of current cancer treatments, especially for tumors resistant to conventional methods. The UCLA team is now preparing for the first human clinical trial to evaluate the safety and efficacy of LRRC15-targeted radiotheranostics in metastatic osteosarcoma patients, with plans to start later this year.