RET, or rearranged during transfection, is a receptor tyrosine kinase implicated in multiple oncogenic processes. Historically studied in thyroid and lung cancers, RET’s relevance to neuroendocrine prostate cancer had remained unexplored until recent investigations identified its overexpression in NEPC tumors. This discovery opened new avenues for the development of targeted molecular tools capable of binding RET with high specificity and affinity. Researchers built upon this foundation by engineering RET-binding peptides designed to serve dual functions: enabling high-contrast positron emission tomography (PET) imaging and delivering therapeutic payloads in the form of radioligand therapy.

The research team, led by Dr. Yongxiang Tang from Xiangya Hospital, Central South University in China, meticulously validated RET as a robust biomarker for NEPC through immunohistochemical analysis of 134 human prostate tissue samples. Their findings confirmed a stark contrast in RET expression between neuroendocrine and non-neuroendocrine prostate cancer specimens, underscoring RET’s potential as a differentiating molecular target. This facilitated the selection of RET-L7, a peptide exhibiting strong and selective binding to the RET receptor, forming the foundation for the theranostic agents developed.

For imaging applications, the peptide RET-L7 was conjugated with the chelator DOTA and radiolabeled with Gallium-68 (^68Ga), creating [^68Ga]Ga-DOTA-RET-L7. This radiotracer demonstrated exceptional capability in targeting RET-positive tumors in preclinical xenograft models, enabling high-contrast PET imaging. The specificity of tumor uptake was verified through blocking studies, indicating minimal off-target accumulation and rapid systemic clearance, properties crucial for optimizing image resolution and patient safety. This represents a transformative advance over PSMA-based imaging, which often fails to detect NEPC lesions due to low or absent PSMA expression.

Complementary to diagnostic imaging, the therapeutic counterpart was developed by labeling DOTA-RET-L7 with Lutetium-177 (^177Lu), a beta-emitting radionuclide that delivers cytotoxic radiation to tumor cells upon receptor-mediated internalization. In preclinical experiments, a single dose of [^177Lu]Lu-DOTA-RET-L7 demonstrated a clear, dose-dependent prolongation of survival in mice bearing RET-positive tumors. Importantly, comprehensive toxicity assessments revealed no significant hematologic or organ-related side effects, highlighting the safety profile of this targeted radioligand therapy.

Dr. Tang emphasized the clinical implications of these findings: “Our data validate RET as a selective surface marker unique to neuroendocrine prostate cancer, enabling both superior imaging and effective radioligand therapy in preclinical models. This research lays the groundwork for translating a RET-targeted theranostic approach into clinical settings, especially for patients whose tumors are PSMA-negative and thus poorly served by current imaging and therapeutic modalities.” The ability to precisely visualize and treat NEPC could markedly improve patient outcomes by facilitating earlier and more accurate disease management.

Currently, the research team is advancing toward first-in-human imaging trials under an investigator-initiated protocol, signaling a pivotal step in the translational pathway. This phase will ascertain critical parameters such as dosimetry, safety, and optimal imaging windows. Wider clinical adoption of RET-targeted theranostics will require robust validation in larger cohorts, rigorous safety evaluations, and regulatory approvals. Nonetheless, these early results herald a promising new paradigm for tackling a cancer subtype that has long defied conventional molecular targeting strategies.

The impact of this theranostic innovation extends beyond neuroendocrine prostate cancer. It elucidates a framework for identifying and exploiting unique biomarkers in other aggressive, treatment-resistant cancers that escape routine diagnostic detection. By integrating precision molecular imaging with targeted radiotherapy, this approach exemplifies the evolving field of personalized medicine, wherein diagnostic and therapeutic interventions are tailor-made to the molecular fingerprint of an individual’s tumor.

Moreover, the successful application of peptide ligands as vectors for both imaging and therapy underscores the versatility of peptide chemistry in nuclear medicine. Their small size, rapid systemic kinetics, and high specificity make peptides excellent candidates for theranostic development, as exemplified by RET-L7. These characteristics translate to superior imaging contrast, minimized off-target toxicity, and effective tumor eradication, synergistically enhancing diagnostic confidence and therapeutic efficacy.

The potential clinical benefits are profound. Patients with NEPC face a dismal prognosis due partly to diagnostic challenges that delay treatment initiation. The novel RET-targeted PET tracer offers a lifeline by illuminating tumors previously obscured by the limitations of PSMA imaging. Coupled with targeted radioligand therapy, clinicians could simultaneously pinpoint, treat, and monitor tumor response with unprecedented precision, ultimately elevating standards of care.

In summary, the identification and validation of RET as a selective biomarker for neuroendocrine prostate cancer, combined with the engineering of RET-binding peptides for PET imaging and radioligand therapy, represent a monumental stride forward in nuclear medicine. This theranostic approach circumvents the shortcomings of PSMA-directed strategies, offering new hope for patients afflicted by one of the most lethal prostate cancer variants. As the research progresses toward clinical application, it underscores the power of molecular insight combined with cutting-edge imaging and therapeutic technologies in transforming cancer care.

Subject of Research: Neuroendocrine Prostate Cancer Theranostics Targeting RET Biomarker

Article Title: RET-Targeted Theranostic Peptides Enable PET Imaging and Radioligand Therapy of Neuroendocrine Prostate Cancer

News Publication Date: 2026

Web References:

• Society of Nuclear Medicine and Molecular Imaging 2026 Annual Meeting Abstract: https://www.xcdsystem.com/snmmi/program/UtDKfSi/index.cfm?pgid=3058&sid=53916&mobileappid=5391600000
• Society of Nuclear Medicine and Molecular Imaging: http://www.snmmi.org/

References: Tang Y, Xiao L, Yang J, Hu S, Rominger A, Shi K. RET-Targeted Theranostic Peptides Enable PET Imaging and Radioligand Therapy of Neuroendocrine Prostate Cancer. Presented at SNMMI 2026.

Image Credits: Courtesy of SNMMI

Keywords: Neuroendocrine prostate cancer, RET biomarker, PET imaging, radioligand therapy, theranostics, [^68Ga]Ga-DOTA-RET-L7, [^177Lu]Lu-DOTA-RET-L7, PSMA-negative prostate cancer, molecular imaging, personalized medicine

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