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Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice
Published on: December 21, 2019
PET radiotracers targeting MDM2 protein interaction: From preclinical validation to first-in-human studies
Chengxue He1, Zhen Wang2, Nina Zhou1
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, China.
Abstract:
Current imaging techniques inadequately delineate surgical margins of well-differentiated liposarcoma (WDLS), increasing risks of incomplete resection or overtreatment. MDM2, a p53-inhibiting oncoprotein amplified in WDLS, represents a dual diagnostic and therapeutic target. Therefore, we developed two radionuclide probes utilizing the MDM2-targeting stapled peptide with high binding affinity to evaluate their suitability for tumor-specific diagnostic purposes, which named [68Ga]Ga-DOTA-7041 and [68Ga]Ga-DOTA-P53-8 to conduct a head-to-head comparative study. Among these, [68Ga]Ga-DOTA-7041 showed superior MDM2-binding affinity (6.7 nM). In vivo imagery in ccRCC tumor-bearing PDX models showed significant and rapid uptake for both radiotracers, with specific radioactive accumulation beginning at 10 min and persisting over time. In contrast, the SW872 liposarcoma mouse model demonstrated slower and lower uptake, visible at 4 h in PET/CT scans. The further Clinical PET/CT in a WDLS patient using the superior probe [68Ga]Ga-DOTA-7041 showed heterogeneous tumor uptake, correlating with postoperative MDM2 immunohistochemistry. In this study, [68Ga]Ga-DOTA-7041 demonstrated diagnostic potential in both animal models and patients with liposarcoma as first-in-human PET tracer targeting MDM2. The disparate tumor uptake observed, compared to the high uptake in renal cancer models, may provide valuable insights into the challenges of targeting MDM2/MDMX with therapeutic agents in liposarcoma treatments.
Insights
New radionuclide probes targeting MDM2 show promise for diagnosing well-differentiated liposarcoma (WDLS). [68Ga]Ga-DOTA-7041 demonstrated diagnostic potential in preclinical models and a patient, offering insights for future liposarcoma treatments.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Current imaging methods struggle to accurately define surgical margins for well-differentiated liposarcoma (WDLS).
- MDM2 oncoprotein is a key target in WDLS, implicated in both diagnosis and therapy.
- Developing specific imaging probes is crucial for improving WDLS management.
Purpose of the Study:
- To develop and compare two novel MDM2-targeting radionuclide probes, [68Ga]Ga-DOTA-7041 and [68Ga]Ga-DOTA-P53-8, for WDLS diagnosis.
- To evaluate the in vivo diagnostic potential of these probes in preclinical models and a human patient.
- To assess the diagnostic accuracy and tumor specificity of the superior probe, [68Ga]Ga-DOTA-7041.
Main Methods:
- Synthesis and characterization of two MDM2-targeting stapled peptide-based radiotracers: [68Ga]Ga-DOTA-7041 and [68Ga]Ga-DOTA-P53-8.
- Head-to-head comparison of probe binding affinity and in vivo performance using PET/CT imaging in clear cell renal cell carcinoma (ccRCC) and liposarcoma (SW872) xenograft models.
- First-in-human clinical PET/CT imaging of a WDLS patient using the lead probe, [68Ga]Ga-DOTA-7041, followed by correlation with postoperative MDM2 immunohistochemistry.
Main Results:
- [68Ga]Ga-DOTA-7041 exhibited superior MDM2-binding affinity (6.7nM) compared to [68Ga]Ga-DOTA-P53-8.
- Both probes showed rapid and significant uptake in ccRCC models, with specific accumulation observed early and persisting over time.
- In liposarcoma models, uptake was slower and lower, becoming visible at 4 hours. The clinical PET/CT scan in a WDLS patient revealed heterogeneous tumor uptake for [68Ga]Ga-DOTA-7041, consistent with MDM2 expression.
- [68Ga]Ga-DOTA-7041 demonstrated diagnostic potential in both animal models and a WDLS patient.
Conclusions:
- [68Ga]Ga-DOTA-7041 is a promising first-in-human PET tracer for MDM2-targeted imaging in liposarcoma.
- The probe's performance in WDLS differs from its uptake in renal cancer models, suggesting potential challenges for MDM2/MDMX-targeted therapies in liposarcoma.
- This study highlights the diagnostic utility of [68Ga]Ga-DOTA-7041 and provides insights into MDM2-targeted strategies for liposarcoma.
