Novel theranostic approach targets aggressive neuroendocrine prostate cancer

A novel theranostic approach that targets RET -- a newly identified biomarker for neuroendocrine prostate cancer enables high-contrast PET imaging and effective, safe treatment for this highly aggressive malignancy. Because this disease is often poorly visualized with prostate-specific membrane antigen (PSMA)-based imaging, the RET approach offers an important alternative when conventional molecular imaging and PSMA-directed therapies are unsuitable. This research was presented at the Society of Nuclear Medicine and Molecular Imaging 2026 Annual Meeting.

Neuroendocrine prostate cancer is an aggressive, treatment-resistant subtype that frequently develops as an evolution of castration-resistant prostate cancer. It often expresses low levels of PSMA or is PSMA negative. Consequently, the disease is difficult to detect with current PSMA-based imaging, leading to less effective treatment.

Patients with neuroendocrine prostate cancer face a major challenge because this cancer can hide from PSMA-based scans and therapies. In our study, we aimed to identify a neuroendocrine prostate cancer biomarker and develop a theranostic pair for PET imaging and radioligand therapy."

Yongxiang Tang, associate professor and deputy director, Department of Nuclear Medicine, Xiangya Hospital, Central South University, in Changsha, Hunan, China

Based on previous studies, researchers identified RET as a candidate surface marker, and RET expression was validated by immunohistochemistry in 134 human prostate specimens. Upon selecting RET-L7 as a binding peptide, ⁶⁸Ga-DOTA-RET-L7 PET/CT and ¹⁷⁷Lu-DOTA-RET-L7 therapy were evaluated in RET-positive and RET-negative xenografts, and blocking, biodistribution, survival, and toxicity studies were conducted.

⁶⁸Ga-DOTA-RET-L7 demonstrated high, specific uptake in RET-positive tumors versus RET-negative tumors, with strong self-blockade and rapid blood clearance. A single dose of ¹⁷⁷Lu-DOTA-RET-L7 produced dose-dependent survival benefit without significant hematologic or organ toxicity.

"RET is a clinically relevant neuroendocrine prostate cancer-selective surface target," said Tang. "This preclinical work supports translation of the RET-targeted theranostic approach for PSMA-negative prostate cancer."

The research continues to move forward as first-in-human imaging is currently being conducted as part of an investigator-initiated clinical study. Broader patient access will require additional safety and dosimetry evaluation, larger clinical validation, and regulatory approvals.