At Xiangya Hospital in Changsha, Hunan, researchers have cracked a problem that has long eluded prostate cancer treatment: finding and fighting a particularly aggressive form of the disease that evades the imaging and therapies doctors rely on most.
Neuroendocrine prostate cancer is a brutal subtype that emerges as castration-resistant prostate cancer evolves. It spreads quickly and resists treatment far more stubbornly than conventional prostate cancer. The tragedy is that it often expresses little to no PSMA—prostate-specific membrane antigen—the molecular target that has become standard in modern prostate cancer imaging and therapy. For patients with this form of the disease, current tools essentially fail to see what they're looking for, leaving treatment options limited and outcomes grim.
"Patients with neuroendocrine prostate cancer face a major challenge because this cancer can hide from PSMA-based scans and therapies," explains Yongxiang Tang, associate professor and deputy director in the Department of Nuclear Medicine at Xiangya Hospital. His team decided to solve this by finding a different target altogether.
Tang and his colleagues identified RET as a promising alternative biomarker. Working from previous research, they validated RET expression across 134 human prostate tissue samples using immunohistochemistry, establishing that this marker appeared consistently in neuroendocrine prostate cancer. They then developed a theranostic pair—a dual-action tool that diagnoses and treats simultaneously—using RET-L7 as their binding peptide.
The imaging component, 68Ga-DOTA-RET-L7, showed remarkable precision in PET scanning. In preclinical studies, it produced strong, specific uptake in RET-positive tumors while showing minimal uptake in RET-negative tumors. The tracer cleared rapidly from the bloodstream, creating high-contrast images that made tumors stand out vividly. The treatment counterpart, 177Lu-DOTA-RET-L7, proved equally promising. A single dose delivered dose-dependent survival benefit in animal models without causing significant damage to blood cells or vital organs—a critical finding that suggests the therapy could be both effective and tolerable.
"RET is a clinically relevant neuroendocrine prostate cancer-selective surface target," Tang says of their findings. "This preclinical work supports translation of the RET-targeted theranostic approach for PSMA-negative prostate cancer."
The implications are substantial for a patient population that has few alternatives. Rather than facing undetectable disease and limited treatment options, patients with PSMA-negative neuroendocrine prostate cancer could now access imaging that actually reveals their tumors and a therapy designed specifically to target them. The approach offers hope precisely when conventional molecular imaging and drug strategies fall short.
The research is already moving toward clinical reality. First-in-human imaging studies are currently underway as part of an investigator-initiated clinical trial at the hospital. Broader patient access will require additional safety evaluations, dosimetry studies, larger clinical trials, and regulatory approvals—the standard pathway that ensures new therapies are both safe and effective before they become widely available. But the preclinical foundation is solid, and the clinical pathway has begun.