A radiotheranostic approach designed to combat aggressive cancers

UCLA scientists, together with a team of international collaborators, have identified a promising new treatment strategy that can detect, kill and reprogram aggressive, treatment-resistant tumors like osteosarcomas and glioblastoma.

The findings, published in the journal Signal Transduction and Targeted Therapy, describe a novel approach that uses a specially engineered antibody, called DUNP19, to target a protein called LRRC15 that is found on the surface of certain aggressive cancer cells and the supportive stroma cells surrounding them. By pairing the antibody with radioactive particles, scientists can both visualize tumors for precise imaging and deliver targeted radiation therapy directly to cancerous tissue, while sparing healthy tissues.

When tested in mice, the LRRC15-targeted radionuclide therapy effectively slowed tumor growth, extended survival, and altered the tumor microenvironment to make it more receptive to an immune attack.

“Pairing the antibody with radiation creates a powerful ‘radiotheranostic’ approach, where the same targeted antibody, DUNP19, can be loaded with different radioactive particles for both diagnostic and therapeutic purposes,” said Dr. David Ulmert, associate professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA, and senior author of the study.

“This two-pronged approach is especially potent because it offers exquisite control over the radiation’s strength—mild for safe scanning, intense for killing—resulting in fewer side effects than broad chemotherapy or external beam radiation, while improving diagnosis, staging, and treatment of difficult cancers like osteosarcoma and glioblastoma by reprogramming the tumor’s immune-resistant environment.”

Osteosarcoma, the most common form of bone cancer, and glioblastoma, the deadliest type of brain tumor, are notoriously resistant to standard treatments. Their ability to adapt and thrive is fueled by aggressive tumor cells and a dense, fibrous environment that blocks immune responses, which is a hallmark of tumors expressing the LRRC15 protein that DUNP19 was designed to target.

LRRC15 is activated by a growth factor known as TGFβ, which helps tumors grow, spread and resist treatments like immunotherapy. Because LRRC15 is largely absent from healthy tissue, targeted drugs—like radioactive antibodies—can attack tumors specifically by killing cancer cells and weakening the tumor’s defenses, making it an ideal target for this new approach.

Building on this insight, the UCLA team developed DUNP19, a monoclonal antibody that binds tightly to LRRC15 on cancer and stroma cells that fuel tumor growth, and is then rapidly absorbed by tumor cells.

“This lets DUNP19 precisely deliver molecules for detection or toxic agents to detect or kill tumors from within—unlike many existing antibodies that mainly block signals or flag cells for immune attack on the surface,” said Ulmert, who is a member of the UCLA Health Jonsson Comprehensive Cancer Center.

Then, when paired with the radioactive isotope Lutetium-177, the antibody functions like a guided missile, delivering targeted radiation that kills LRRC15-expressing cancer cells and stroma cells.

In preclinical studies, the team tested the therapy in mouse models of osteosarcoma, glioblastoma, triple-negative breast cancer, and aggressive colorectal cancer, which express LRRC15 at varying levels. They tracked tumor growth, survival, and changes in the tumor microenvironment, while analyzing gene activity in both cancer cells and surrounding stromal tissue. This allowed the team to measure not only the antibody’s direct tumor-killing effects but also its ability to alter the tumor environment and make it more receptive to immune attack, an important step toward improving treatment outcomes.

The researchers found that in all the cancer models, DUNP19 carrying radioactive particles cured, slowed tumor growth or extended survival. In osteosarcoma models, nearly all mice bearing tumors that were created in the bone environment showed no signs of disease after treatment, while untreated tumor models succumbed as a result of the disease. Tumors generated in soft tissues, resembling metastatic disease, stopped growing and were harvested for genomic analysis. Similarly, in glioblastoma models, radioactive LRRC15 targeted with DUNP19 prevented further tumor growth and studies were terminated in order to analyze changes that the drug induced.

A corresponding study approach was used for assessing the therapeutic and tumor environmental effects in triple-negative breast cancer tumors. Using computer analysis to look at the tumor tissue after treatment, the researchers found that the LRRC15-targeted radiotherapy eliminated key cells in the tumor, preventing immunotherapy from successfully targeting and destroying the cancer.

In addition, just a single low dose of this LRRC15-targeted radiation therapy significantly boosted immunotherapy’s effectiveness, leading to strong and long-lasting results in mouse models.

“This therapy kills LRRC15-producing stromal cells, breaking down that shield, reprogramming the environment to allow immune cell infiltration, and making other treatments more effective,” Ulmert said.

Beyond slowing tumor growth, DUNP19 reprogrammed the tumor microenvironment, reducing the density of LRRC15-expressing stromal cells and allowing immune cells such as CD8⁺ T cells and natural killer cells to infiltrate previously protected tumors. Gene analysis revealed downregulation of immune-suppressive pathways and upregulation of genes linked to T-cell activation, suggesting the treatment not only attacks tumor cells directly but also primes the tumor for immune-mediated destruction.

“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 Ulmert.

A team led by UCLA’s Dr. Noah Federman is now preparing to launch a first-in-human clinical trial to test the LRRC15-targeted radiotheranostic therapy in patients with metastatic osteosarcoma. That trial is expected to open later this year.

The study’s co-first author is Claire Storey, a graduate student in the Ulmert laboratory. Other UCLA authors are Henan Zhu, Julie Park, Haley Marks, Alexander Ridley, Constance Yuen, Liqun Mao, Michael Cheng, Noah Federman, Johannes Czernin, Laurent Bentolila, Xia Yang, Thomas Graeber and Robert Damoiseaux.