UCLA

The field of radioimmunotheranostics (RIT) has emerged as a powerful strategy for targeted cancer treatment, combining the specificity of monoclonal antibodies with the cytotoxic effects of radionuclides. By leveraging tumor-associated antigens, RIT enables precise imaging, targeted radiotherapy, and immune modulation, offering a promising approach for overcoming therapeutic resistance in aggressive cancers. However, a key component to the success of RIT is in finding disease-driven biomarkers that are representative of the disease state and underlying signaling mechanisms. In prostate cancer (PCa), androgen receptor (AR) signaling remains a critical driver of disease progression and resistance. [89Zr]11B6-PET, a novel imaging modality targeting AR-dependent, prostate-specific protein human kallikrein 2 (hK2), effectively assesses AR pathway activation and therapy-induced changes in PCa mouse models. Additionally, Leucine-rich repeat-containing protein 15 (LRRC15) has been identified as a key biomarker and therapeutic target in aggressive tumors. The humanized monoclonal antibody DUNP19, radiolabeled with Lutetium-177, enables precise imaging and radiotherapy of LRRC15-expressing tumors and cancer-associated fibroblasts (CAFs), leading to tumor suppression and immune reprogramming. Fianlly, the key pro-tumorigenic cytokine transforming growth factor beta, or TGFβ, upregulates LRRC15 expression, contributing to immune evasion and metastasis. Integrative functional and genomic analyses identify key regulators—MMP2, SPARC, TGFβR2, and WNT5B—governing TGFβ-induced LRRC15 expression and immunotherapy resistance. These findings highlight the potential of RIT-based AR and LRRC15-targeted strategies in advancing precision oncology and improving patient outcomes.