A groundbreaking theranostic strategy targeting RET, an emergent biomarker specific to neuroendocrine prostate cancer (NEPC), promises to revolutionize the diagnosis and treatment of this aggressive malignancy. Newly disclosed research from Xiangya Hospital at Central South University, presented at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2026 Annual Meeting, offers compelling evidence for a dual-purpose molecular approach that enables high-contrast positron emission tomography (PET) imaging combined with targeted radioligand therapy. This innovative method is especially significant given the limited sensitivity of current prostate-specific membrane antigen (PSMA)-based diagnostics for NEPC, which often evades detection due to diminished or absent PSMA expression.
Neuroendocrine prostate cancer represents a particularly challenging subset of prostate malignancies. It arises commonly as a transformation from castration-resistant prostate cancer and is known for its rapid progression and resistance to standard treatments. The diagnostic hurdle posed by NEPC lies primarily in its molecular profile, as this subtype frequently exhibits low or negative PSMA levels, resulting in suboptimal visualization with PSMA-targeted imaging agents. Consequently, patients are at a disadvantage, with diagnostic ambiguity potentially delaying or precluding appropriate therapeutic interventions.
Recognizing the clinical impasse imposed by PSMA-negative tumors, the research team, led by oncologist and nuclear medicine specialist Yongxiang Tang and colleagues, embarked on a quest to identify an alternative surface biomarker that could serve as both a diagnostic beacon and a therapeutic target. Their investigations pinpointed the receptor tyrosine kinase RET (rearranged during transfection), a cell surface protein previously implicated in various neuroendocrine tumors, as a candidate marker. RET’s selective overexpression on NEPC cells opened the door to novel molecular targeting strategies.
To translate this discovery into actionable clinical tools, the researchers designed and synthesized a novel peptide ligand, dubbed RET-L7, renowned for its high-affinity binding to the RET receptor. Leveraging the molecular versatility of RET-L7, they created a theranostic pair by chemically conjugating this peptide with two different radionuclides: a gallium-68 isotope for PET imaging, and a lutetium-177 isotope for radioligand therapy. This dual approach facilitates seamless integration of tumor detection and targeted treatment within the same molecular framework.
Extensive validation of RET expression was performed using immunohistochemical analyses across 134 human prostate tissue specimens, ensuring the biomarker’s specificity and prevalence in NEPC. Subsequent preclinical experiments employed xenograft models implanted with RET-positive and RET-negative tumor cells to assess the diagnostic efficacy and therapeutic impact of the radiolabeled peptide conjugates. PET imaging with ^68Ga-DOTA-RET-L7 demonstrated superior tumor uptake and contrast in RET-positive xenografts compared to controls, underscoring the tracer’s high specificity and rapid clearance from non-target tissues.
The therapeutic potential of the RET-targeted approach was confirmed through administration of ^177Lu-DOTA-RET-L7 in vivo. This treatment yielded a pronounced, dose-dependent survival benefit, reflecting effective tumor cell eradication without eliciting significant off-target hematologic or organ toxicities. The important balance between therapeutic efficacy and safety signals an encouraging prognostic horizon for patients with NEPC, long burdened by limited treatment options and poor outcomes.
Furthermore, blocking experiments validated the selectivity of RET-L7 binding to its intended target, reinforcing confidence in the mechanism of action driving both imaging and therapeutic capabilities. These findings collectively underscore RET as a clinically actionable surface receptor that holds transformative potential as a theranostic target in prostate cancers refractory to PSMA-directed modalities.
The pioneering work spearheaded by Tang and colleagues sets the stage for imminent human clinical trials. First-in-human imaging studies are already underway as part of an investigator-initiated clinical trial aimed at evaluating safety, dosimetry, and imaging quality in patients with advanced neuroendocrine prostate cancer. Although these initial steps are promising, broader clinical adoption will require comprehensive regulatory review, expanded patient cohorts for validation, and longitudinal assessment of therapeutic outcomes and toxicities.
This RET-centered theranostic platform embodies precision oncology’s fundamental goal: to tailor diagnostics and therapeutics to the unique molecular signature of a patient’s tumor. By circumventing the limitations imposed by PSMA negativity in NEPC, the approach not only enhances tumor visualization but also opens a new therapeutic avenue that could materially improve survival and quality of life. It exemplifies the powerful synergy of molecular imaging and targeted radionuclide therapy in overcoming the biological complexity of resistant cancers.
The work raises intriguing possibilities for expanding RET-targeted diagnostics and therapies beyond prostate cancer, potentially encompassing other neuroendocrine malignancies where RET plays a pathogenic role. It also highlights the value of multidisciplinary collaboration across nuclear medicine, oncology, radiochemistry, and molecular biology to rapidly translate benchside discoveries into clinical innovations that address unmet medical needs.
As the field anticipates further validation studies, this research marks a milestone in molecular oncology. The ability to pinpoint and eradicate elusive cancer cell populations through theranostic peptides tailored to tumor-specific biomarkers heralds a new era in cancer management—one that could bring hope to patients who previously had few effective options. The RET-targeted theranostic paradigm thus represents not only a scientific breakthrough but a beacon of therapeutic promise in the ongoing battle against aggressive prostate cancer variants.
Subject of Research: Neuroendocrine prostate cancer; RET-targeted PET imaging and radioligand therapy
Article Title: RET-Targeted Theranostic Peptides Enable PET Imaging and Radioligand Therapy of Neuroendocrine Prostate Cancer
News Publication Date: 2026
Web References:
https://www.xcdsystem.com/snmmi/program/UtDKfSi/index.cfm?pgid=3058&sid=53916&mobileappid=5391600000
https://web.cvent.com/event/83fe3b95-a605-4d57-94ca-0ca0ac6a1d5e/summary?categories_2e83a474=2e83a474-b79e-412a-8dc3-bf42de3edac4
http://www.snmmi.org/
Image Credits: Courtesy of SNMMI
Keywords: Neuroendocrine prostate cancer, RET biomarker, theranostic peptides, PET imaging, radioligand therapy, ^68Ga-DOTA-RET-L7, ^177Lu-DOTA-RET-L7, targeted radionuclide therapy, prostate cancer imaging, molecular imaging, precision oncology, PSMA-negative prostate cancer
