Cadherin 3(CDH3)-Targeted PET in Lung Malignant Tumors

Overview

Lung malignant tumors are a significant health threat with high incidence and mortality rates, and molecular imaging is crucial for early diagnosis, staging, prognosis evaluation, and therapeutic efficacy assessment. 18F-FDG PET imaging is widely used, but has limitations. CDH3 is a promising target for tumor-targeted imaging, as it is only expressed in cancerous epithelial cells. A new PET probe, 68Ga-TOI-1, targeting CDH3 has been developed with better affinity and selectivity than previous probes. Preclinical data support its safety and metabolic stability, and future research will explore its diagnostic and staging value in different types of lung tumors, providing a new and precise evaluation method for lung malignant tumors.

Cancer is a leading cause of high mortality rates worldwide and a significant barrier to increasing life expectancy. Among various cancer types, lung cancer is one of the most common malignant tumors globally. According to global cancer statistics, as of 2020, the global incidence rate of lung cancer was 11.4%, and the mortality rate was 18%. Lung cancer is a major cause of cancer-related deaths in China and worldwide, particularly non-small cell lung cancer (NSCLC), and its treatment strategies are continuously evolving. Immunotherapy and targeted neoadjuvant therapy can help eliminate micrometastases to reduce postoperative recurrence, lower tumor staging to improve the resectability of primary lesions, and enhance the long-term survival rate of lung cancer patients to some extent. However, for patients with resectable lung cancer, surgery remains the primary curative approach. Given the significant individual variability in lung cancer treatment outcomes, the suboptimal efficacy of traditional PET in monitoring treatment response, and the lack of effective methods for distinguishing benign from malignant pulmonary nodules, there is a critical clinical need for innovative approaches. Leveraging key molecular imaging markers for preoperative assessment of treatment efficacy and assisting in the differentiation of benign and malignant pulmonary nodules is a crucial scientific direction for our research team. In recent years, molecular imaging has been increasingly applied in cancer diagnosis and treatment, with PET molecular imaging emerging as a key tool for lung cancer management. By utilizing targeting moieties of molecular probes to precisely bind to tumor biomarkers, coupled with radiation emitted from radionuclides during decay, it is possible to achieve accurate lesion detection and non-invasive monitoring. This approach holds promise for overcoming longstanding challenges in conventional PET imaging for comprehensive lung cancer treatment, such as high false-positive rates. High-dimensional multi-omics technologies integrate data from genomics, transcriptomics, proteomics, and other levels. By employing transcriptomics and proteomics, overexpressed proteins in lung cancer tissues can be identified at the tissue level, while spatial transcriptomics and single-cell transcriptomics can validate the cellular localization of target proteins. Multi-omics approaches enable systematic exploration of key molecular targets in lung cancer, providing a reliable pathway for precision target discovery. Utilizing a previously established large-scale Chinese multi-omics lung cancer cohort, combined with bioinformatics analysis and in vitro and in vivo molecular biology validation, the investigators identified CDH3 as a surface biomarker for non-small cell lung cancer. Cadherin-3 (CDH3) is a glycoprotein whose abnormal high expression in non-small cell lung cancer is closely associated with poor prognosis, enhanced tumor proliferation and migration, and the formation of an immunosuppressive microenvironment. CDH3 has emerged as a promising novel therapeutic target for lung cancer. Currently, drug development targeting CDH3 primarily focuses on antibody-drug conjugates (ADCs). In a study involving five patients with advanced NSCLC harboring EGFR mutations, these drugs achieved an objective response rate as high as 80%. Through multi-omics imaging target screening, CDH3 was identified as a potential imaging target due to its specific high expression on the surface of lung cancer cells. Supported by a key project from the National Natural Science Foundation of China, our team has previously developed a CDH3-targeted molecular probe, TOI-1, with independent intellectual property rights and has applied for a patent (published under publication number CN121426959A). This probe has demonstrated excellent sensitivity and specificity in preclinical animal models. the investigators are now collaborating with the Department of Nuclear Medicine at our hospital to conduct an exploratory clinical study on the 68Ga-TOI-1 PET molecular probe. 68Ga-TOI-1 PET/CT imaging is expected to help determine the benign or malignant nature of tumors and their extent of involvement, enable tumor localization and qualitative diagnosis, facilitate early diagnosis and restaging of recurrent tumors, and provide scientific evidence for disease staging, disease activity assessment, treatment planning, and prognosis evaluation.