In a promising advancement within cancer therapeutics, researchers at the University of Miami’s Sylvester Comprehensive Cancer Center have unveiled a novel combination therapy that could revolutionize treatment paradigms for advanced neuroendocrine tumors (NETs). Led by Dr. Aman Chauhan, the Neuroendocrine Tumor Program team presented groundbreaking phase 1 clinical trial data at the European Society for Medical Oncology (ESMO) Congress 2025. This new approach pairs a DNA-synthesis inhibitor, specifically a ribonucleotide reductase inhibitor (RRI), with lutetium Lu 177 dotatate—a targeted radiopharmaceutical agent—showing potential synergy in combating gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
Neuroendocrine tumors, though relatively rare, present a significant therapeutic challenge due to their heterogeneous nature and often indolent yet progressive clinical course. These tumors arise from neuroendocrine cells dispersed throughout the gastrointestinal tract and pancreas, areas critical for hormone regulation and digestive functions. Standard treatments have evolved to include lutetium Lu 177 dotatate, a somatostatin receptor-targeted radiolabeled therapy, which has significantly improved outcomes in somatostatin receptor-positive NET patients. However, therapeutic resistance and eventual disease progression remain barriers to durable control in many cases.
The innovative strategy explored in Dr. Chauhan’s study harnesses the mechanistic synergy between the RRI and lutetium Lu 177 dotatate. Ribonucleotide reductase is a vital enzyme facilitating the conversion of ribonucleotides into deoxyribonucleotides—essential precursors for DNA synthesis and repair. By pharmacologically inhibiting this enzyme, the RRI induces impaired DNA replication and repair within tumor cells, sensitizing them to the cytotoxic effects of radiation delivered by the lutetium Lu 177 dotatate. This dual assault disrupts tumor cell survival pathways, potentially overcoming resistance mechanisms that limit current radiopharmaceutical efficacy.
The phase 1 clinical trial, supported by the National Cancer Institute and conducted via the Experimental Therapeutics Clinical Trials Network (ETCTN), primarily assessed safety and tolerability of the combination while observing preliminary signs of anti-tumor activity. Enrolling patients with well-differentiated, progressive GEP-NETs, the study established a clinically manageable toxicity profile, with encouraging biomarkers suggesting enhanced radiopharmaceutical activity in the presence of the DNA synthesis blockade. These findings pave the way for the recently completed phase 2 randomized trial comparing this combination therapy against lutetium Lu 177 dotatate monotherapy.
Neuroendocrine tumors are exhibiting a rising incidence globally, nearly doubling over the past two decades, according to NIH-supported epidemiological studies. Despite better diagnostic tools and improved survival metrics, mortality associated with these cancers continues to increase, underscoring the need for innovative treatment solutions. The integration of DNA synthesis inhibition with targeted radionuclide therapy offers a mechanistically rational approach to improve tumor control and patient outcomes.
Dr. Chauhan emphasizes the role of theranostics—the seamless integration of diagnostic agents and targeted therapeutics—in personalizing oncologic care. By combining these disciplines, clinicians can better select candidates for specific treatments based on receptor expression, tumor biology, and anticipated response to therapy. The RRI and lutetium Lu 177 dotatate regimen exemplifies this approach by tailoring targeted radiation delivery with a molecular agent designed to heighten tumor vulnerability.
The phase 2 randomized trial concluded enrollment at fourteen U.S. sites, positioning researchers to evaluate critical endpoints such as progression-free survival and overall response rates. Success in this trial could establish a new standard of care for patients with advanced GEP-NETs, particularly those who have exhausted existing treatment lines. It also holds promise for stimulating further research efforts exploring combinatorial regimens that integrate DNA replication inhibitors with other types of radiopharmaceuticals.
Beyond its clinical implications, the combination therapy underscores an evolving paradigm in cancer drug development—leveraging cross-disciplinary collaborations between molecular oncology, radiochemistry, and pharmacology. The ongoing support from public health agencies and industry partners like Nanopharmaceutics LLC reinforces the translation of these innovations from bench to bedside, ensuring patients benefit from cutting-edge therapeutic modalities.
At the ESMO 2025 mini oral session devoted to neuroendocrine and endocrine tumors, Dr. Chauhan’s presentation titled “Multi-center NCI-sponsored phase 1 study of Triapine® in combination with 177 Lu-dotatate in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs)” drew significant attention, highlighting its potential to shift existing treatment landscapes. The research community and clinical oncologists alike anticipate the forthcoming phase 2 data with optimism.
This pioneering work also reflects a commitment to addressing the complexity of NETs, which are often overlooked in oncology research. By enhancing radiosensitivity through enzymatic inhibition, this approach may ultimately improve survival outcomes and quality of life for patients who face limited therapeutic options today. The success of this combination therapy could spark novel avenues in the war against neuroendocrine tumors and broaden the arsenal of precision medicine tools available to clinicians.
As the research advances into later-phase trials, the oncology field watches closely, with hopes that this dual-modality strategy can mitigate mechanisms of resistance and translate into meaningful clinical benefit. The future of GEP-NET treatment may well depend on such innovative combinations that integrate molecular targeting with radiation oncology to harness synergistic cytotoxicity.
Subject of Research: Combination therapy using ribonucleotide reductase inhibitor and lutetium Lu 177 dotatate for well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
Article Title: Multi-center NCI-sponsored phase 1 study of Triapine® in combination with 177Lu-dotatate in patients with well-differentiated gastroenteropancreatic neuroendocrine tumours (GEP-NETs)
News Publication Date: October 20, 2025
Web References:
- Sylvester Comprehensive Cancer Center
- ClinicalTrials.gov Phase 1 Trial NCT04234568
- ClinicalTrials.gov Phase 2 Trial NCT05724108
- ESMO 2025 Abstract
- National Institutes of Health Study on NETs
References: National Cancer Institute, Experimental Therapeutics Clinical Trials Network (ETCTN), Nanopharmaceutics LLC
Image Credits: Photo by Sylvester Comprehensive Cancer Center
Keywords: Pancreatic tumors, Cancer research, Clinical research, Drug research
