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Unveiling Novel Therapeutic Targets for Neuroendocrine Cancers: A Precision Medicine Breakthrough

A microplate containing tumoroids, zoomed in image of the individual wells and further magnification of the GEP-NENs tumoroid
Patient-derived Tumoroids (PDTs) - Miniature replicas of tumors cultivated in the laboratory. PDTs are state-of-the-art research tools currently used in precision medicine. Leveraging this innovative approach, we envision advancing therapeutic development and, together with clinicians, pioneering targeted cancer therapies, tailored for individual disease characteristics and individual cancer patients. Credit: Corning® Ultra-Low Attachment Spheroid Microplate, image courtesy of Corning; University of Bern, ex vivo patient-derived tumoroid from GEP-NENs, image acquired by Simon April-Monn, PhD.
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In this breakthrough study published in npj Precision Oncology, we delve into the complexities of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Collaborating with leading international research institutions, including the Charité – Universitätsmedizin Berlin, the University Medical Center Hamburg-Eppendorf, and the Department of Health Sciences and Technology D-HEST ETH Zurich, our team has uncovered promising avenues for personalized anti-cancer therapies. Our paper sheds light on our journey, revealing key insights into the molecular landscape of GEP-NENs and identifying novel therapeutic targets.

Driving precision medicine advances

High-grade GEP-NENs are highly aggressive and heterogenous cancers. The lack of predictive therapeutic biomarkers makes it challenging for clinicians to select treatments and predict clinical courses for individual patients. With limited therapeutic options available, there is a compelling necessity to explore personalized approaches that could revolutionize patient care. Driven by the urgent need for more individualized and effective therapies for neuroendocrine cancer patients, our study aimed to decipher the intricate biology of GEP-NENs from a functional perspective.

Unraveling GEP-NENs: Experimental highlights

Utilizing cutting-edge research techniques, we meticulously dissected the molecular mechanisms underpinning GEP-NENs functional drug response to first-line chemotherapies. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients. We applied this model for targeted rapid ex vivo drug screening, next-generation sequencing and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug responses to patients’ clinical responses to chemotherapy and investigated treatment-induced adaptive stress responses.

The key findings of the paper were:

  • First, detailed molecular and functional insights into the biological complexities of high-grade GEP-NENs.
  • First proof-of-concept and validation of patient-derived tumoroids as a robust translational research tool for rapid ex vivo drug screenings in neuroendocrine cancers.
  • Patient-derived tumoroids recapitulated biological key features of high-grade GEP-NEN and mimicked the clinical response to chemotherapy ex vivo.
  • Identification of two novel therapeutic anti-cancer targets, lysine demethylase 5A (KDM5A) and interferon-beta 1 (IFNB1), auxiliary to first-line chemotherapies.
  • Synergistic enhancement of the efficiency of first-line chemotherapy by the application of targeted combination therapy.

Unlocking therapeutic potential

Our findings offer a deeper understanding of GEP-NENs' underlying biology, and mechanistical and functional perspectives of the adaptive stress response, paving the way for targeted therapies tailored to individual cancer patients. Our data demonstrate that high-grade GEP-NEN PD tumoroids are well suited for rapid ex vivo drug screening with clinically relevant turnaround times of only two weeks. Our work, therefore, focused on high translational impact and clinical relevance and with patient-derived tumoroids we envision being able to provide useful and missing functional information, helping clinicians to select the best therapies for high-grade GEP-NENs. Moreover, by elucidating the synergistic effects of novel anti-cancer therapy targets with cisplatin, we present a promising avenue for improving therapy outcomes in this challenging disease. Our discoveries hold significant implications for precision medicine, offering hope to individual cancer patients. Further validation in clinical settings is warranted to harness the potential of these therapeutic targets fully. While our study provides valuable insights, it is essential to acknowledge its limitations, including the need for clinical validation and potential challenges in translating preclinical findings into clinical practice.

In conclusion, our research lays the groundwork for prospective validation of patient-derived tumoroids as faithful ex vivo models for personalized screening of treatment efficacies.

Charting the course ahead

Moving forward, our focus will be on translating these findings into clinical applications, with an emphasis on conducting rigorous (co)-clinical trials to validate the efficacy of novel therapeutic strategies and the application of rapid ex vivo drug screenings in patient-derived tumoroids. Additionally, further research is needed to explore additional therapeutic targets and refine personalized treatment approaches for GEP-NENs. Overall, with our approach, we envision being able to help advance precision medicine, benefiting cancer patients with individualized therapies in the future.

Reference: April-Monn SL. et al. Patient derived tumoroids of high grade neuroendocrine neoplasms for more personalized therapies. npj Precis. Onc. 8, 59 (2024). doi:10.1038/s41698-024-00549-2