Clinical Application of PET Imaging Targeting GPA33 in Malignant Tumors

Malignant tumors are one of the major diseases leading to death worldwide, and their high incidence and mortality rates pose a serious threat to human health. According to the World Health Organization (WHO), there will be about 19.3 million new cancer cases and 10 million deaths globally in 2020, with a significant increase in the incidence of malignant tumors such as colorectal and gastric cancers in particular. Early diagnosis and load assessment of tumors are crucial for improving patient survival.Currently, there are limitations in the commonly used clinical diagnostic imaging tools. For example, traditional anatomical imaging techniques (e.g., ultrasound, CT, and MRI) have high resolution in displaying the anatomical structure of tumors, but it is difficult to accurately differentiate between benign and malignant lesions, and is not sufficiently sensitive to the performance of some tumors rich in fibrotic and necrotic tissues. Enhanced magnetic resonance imaging (ceMRI) has limited effectiveness in the detection of certain solid tumors, and is particularly deficient in the identification of microscopic lesions and some deep tumors. [18F]FDG PET/CT, a current widely used molecular imaging technique, enables functional imaging of tumors by reflecting the level of glucose metabolism. However, [18F]FDG is not a tumor-specific imaging agent, and non-malignant lesions such as inflammation, infection, and tuberculosis can also lead to an increase in local FDG uptake, producing false-positive results. In addition, [18F]FDG uptake is low in some tumors with low metabolic activity (e.g., poorly differentiated carcinomas and some brain tumors), leading to false-negative results and limiting its use in early tumor diagnosis and precision assessment. Therefore, the development of more specific and sensitive molecular imaging probes has significant clinical value. GPA33 is a member of the immunoglobulin superfamily, and as a novel transmembrane glycoprotein, it is significantly expressed in more than 95% of colorectal cancers, and mildly expressed in normal intestinal mucosa, as well as showing different degrees of expression in gastric and pancreatic cancers. Studies have shown that GPA33 has the functions of cell surface recognition and adhesion, as well as triggering intercellular signaling and immune response. These features make it has gradually become a potential marker for tumor diagnosis and treatment. In recent years, breakthroughs have been made in the research of targeted drugs against GPA33. However, how to screen patients suitable for targeted GPA33 therapy and dynamically evaluate the therapeutic effects remain clinical challenges. Therefore, the development of molecular imaging probes targeting GPA33 and the realization of non-invasive, real-time quantitative detection of GPA33 expression by PET imaging are expected to provide an imaging basis for targeted therapy. This can not only be used to screen patient groups with high GPA33 expression, thus accurately guiding the clinical application of targeted drugs, but also to assess drug efficacy in real time during the treatment process and promote the implementation of individualized treatment plans. In summary, the aim of this project is to explore the clinical application of PET imaging technology targeting GPA33 in malignant tumors, through PET imaging agents targeting GPA33 ([68Ga]Ga-NOTA-GPA33 nanobody as an example), with a view to be used for the diagnosis and staging of patients with malignant tumors, assessing the tumor load and the abundance of GPA33 expression, and assisting in the determination of the therapeutic regimen. Preliminary pharmacokinetic analysis was also performed in healthy volunteers to clarify the metabolic pattern and adverse effects of the drug in vivo.