Radiotheranostic Approach Detects, Kills and Reprograms Aggressive Cancers

Aggressive cancers such as osteosarcoma and glioblastoma often resist standard therapies, thrive in hostile tumor environments, and recur despite surgery, radiation, or chemotherapy. These tumors also block immune responses, making treatment even more challenging. To address this unmet need, scientists have developed a radiotheranostic strategy that detects, kills, and reprograms aggressive, treatment-resistant tumors.

A team from the David Geffen School of Medicine at UCLA (Los Angeles, CA, USA), in collaboration with global research partners, designed an LRRC15-targeting monoclonal antibody called DUNP19 that binds tightly to cancer and stromal cells expressing the LRRC15 protein — a marker found across highly aggressive and treatment-resistant tumors. The approach works by pairing DUNP19 with radioactive particles.

This enables a dual action: mild radiation for imaging and stronger radiation for targeted treatment. LRRC15 is activated by the TGFβ growth factor and drives tumor growth, immune resistance, and metastasis. Because LRRC15 is scarce in healthy tissues, DUNP19 can precisely deliver radiation to tumors while sparing surrounding organs. The antibody is rapidly absorbed by target cells, allowing internal delivery of diagnostic tracers or therapeutic isotopes such as Lutetium-177.

In preclinical testing, researchers studied osteosarcoma, glioblastoma, triple-negative breast cancer, and aggressive colorectal cancer models expressing LRRC15 at different levels. The radiotheranostic therapy slowed tumor progression, extended survival, or completely halted tumor growth depending on the model. In bone-based osteosarcoma, nearly all treated mice showed no signs of disease, while untreated mice succumbed. In soft-tissue and metastatic models, treated tumors stopped growing and were harvested for genomic analysis.

In glioblastoma, tumor growth was halted. The treatment also eliminated stromal cells, shielded tumors from immune attack, and enhanced the penetration of CD8+ T cells and natural killer cells. Gene-expression analysis showed reduced immune-suppressive signaling and increased markers of T-cell activation. Importantly, a single low dose significantly strengthened the effectiveness of immunotherapy, producing durable responses in mice.

These findings, published in the journal Signal Transduction and Targeted Therapy, highlight potential clinical applications for hard-to-treat cancers. By simultaneously imaging, treating, and altering the tumor environment, the therapy offers a multifaceted solution that could benefit patients who do not respond to existing treatments. A first-in-human clinical trial led by UCLA investigators will soon evaluate the LRRC15-targeted radiotheranostic therapy in individuals with metastatic osteosarcoma.

“This new radiotheranostic approach shows promise in mouse models by halting cancer growth, extending survival with minimal side effects, and enhancing immunotherapy—potentially aiding more patients where existing treatments fall short,” said Dr. David Ulmert, senior author of the study.

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