Clinical Application of PET Imaging Targeting MSLN in Malignant Tumors

Malignant tumors are a major public health problem affecting global health. According to Globocan data, in 2020, there will be about 19.3 million new cases of malignant tumors and 9.9 million deaths worldwide. In China, there will be about 1.56 million new cases and 910,000 deaths, ranking first in the world. The global burden of disease is dominated by the burden of cancer, which will continue to increase globally for at least the next 20 years. However, in the early stages, most cancers are largely asymptomatic or have only a few nonspecific symptoms, including fever, nausea, vomiting, changes in stool characteristics, cough, etc., which are often overlooked, and therefore, exploring new strategies for the early and accurate diagnosis of malignant tumors has a crucial role to play in improving the prognosis of patients. Mesothelin (MSLN) is a glycosylphosphatidylinositol-anchored protein that is expressed at low levels in healthy mesothelial tissues (pleura, peritoneum, pericardium) but appears to be highly expressed in many cancer cells, especially in cancers characterized by invasiveness and poor prognosis, including pancreatic, ovarian, and lung adenocarcinomas. Preclinical studies have shown that MSLN expression has a positive role in malignant transformation and chemoresistance through the Wnt/NF-κB/ERK1/2/Akt signaling pathway. Abnormal expression of MSLN plays an important role in tumor cell growth, invasion and metastasis. Meanwhile, MSLN overexpression can activate the PI3K pathway and induce drug resistance in pancreatic cancer cells. In addition, MSLN has become a popular target for targeted antitumor therapy due to its high differential expression, including monoclonal antibodies, antibody drug combinations (ADCs), radioimmunotherapy (RIT), and CAR-T cellular immunotherapy for mesothelioma. Several antibody-drug conjugates (ADCs) against MSLN have been developed, such as LMB-100 (also known as RG7787) as an antibody-drug coupling targeting MSLN, which has been effective in terms of efficacy.Haas et al. utilized lentiviral transduction of chimeric antigen receptor (CAR)-modified autologous T-cells to target anti-MSLN in patients with malignant pleural mesothelioma, ovarian cancer and pancreatic cancer patients, and the results proved to be safe and feasible. Therefore, MSLN is an important target for precise diagnosis and treatment of malignant tumors.

Currently, high-quality, accurate imaging, multiphase computed tomography (CT) and magnetic resonance imaging (MRI) are widely used for detection, staging, and treatment planning. However, CT and MRI scans frequently detect lesions that cannot be further defined, and enhanced CT and enhanced MR also remain limited to morphological features of the tumor. This leads to uncertainty in the diagnosis or extent of disease. For example, overlapping imaging of adenocarcinoma of the pancreas and chronic pancreatitis has led to an indistinguishable misdiagnosis rate of up to 25%. Although endoscopic retrograde cholangiography and cholangiography may provide additional evidence of inflammatory etiology rather than malignancy, these methods are invasive, carry the risk of tumor dissemination along the needle tracks, and may also have a false-negative rate of up to 60%. FDG is a nonspecific tumor imaging agent. Because the energy metabolism of lymphocytes, monocytes, and other inflammatory cells during phagocytosis is also dominated by anaerobic glycolysis, proliferative lesions such as infections and granulomas, and nonmalignant lesions such as benign tumors, may also show high uptake of [18F]FDG. False-positive PET/CT cases are mainly inflammatory lesions of the pancreas (autoimmune pancreatitis, chronic pancreatitis), and granulomatous lesions (pancreatic tuberculosis). Compared with the conventional imaging agent [18F]FDG. 68Ga-labeled Fibroblast Activation Protein (FAP) inhibitors have higher uptake in tumor and lower uptake in other normal tissues, resulting in a higher Target-to-Background Ratio (TBR), which is conducive to improving their sensitivity in detecting tumor. However, 68Ga-FAPI-04 is not a tumor-specific imaging agent, and fibrosis caused by some other benign lesions may also lead to increased FAP expression. Xiaoli Lan, Kirienko M et al. showed that FAP is also expressed in pancreatic α-cells, which is another important factor limiting the use of 68Ga-FAPI-04 in the diagnosis of pancreatic cancer. With the growth of MSLN-targeted therapies in the field of oncology, the development of MSLN-targeted PET imaging strategies as companion diagnostics will hopefully optimize MSLN-targeted therapies. Lamberts LE et al. used 89Zr-MMOT0530A PET to visualize pancreatic and ovarian cancer lesions and antibody biodistribution, a technique that could potentially guide personalized antibody-based therapy. Linda N. Broer's study revealed the potential of 89Zr-MSLN PET to respond to MSLN expression and 227Th-MSLN tumor uptake and biodistribution, demonstrating the potential of 89Zr-MSLN PET as a tool for predicting 227Th-MSLN antitumor activity. Hou's study revealed that the 124I-anti-MSLN probe demonstrated a rapid metabolic rate and the ability to specifically identify MSLN-positive tumors in vivo.

To sum up, this project carries out integrated PET/MR or PET/CT visualization of patients with clinically suspected or diagnosed pancreatic cancer, ovarian cancer, lung adenocarcinoma and other malignant tumors with high expression of MSLN and healthy volunteers, using targeted MSLN-specific imaging agents ([68Ga]Ga-NOTA-MSLN antibody fragment for example), with a view to achieving the following purposes: (1) Patients with malignant tumors: for diagnosis and staging of diseases, comparing with the gold standard pathological diagnosis, assessing diagnostic efficacy, clarifying the presence or absence of lesions, and judging the location and nature of lesions; comparing with [18F]FDG PET for accurate staging, evaluating the tumor load, and helping to determine the treatment plan. (2) Healthy volunteers: Pharmacokinetic analysis will be performed to clarify the metabolic pattern and adverse reactions of the drug in the body.