Mesothelin is a protein found on the surface of cells. It is present in limited amounts on normal mesothelial cells, which line various internal organs such as the pleura (lungs), pericardium (heart), and peritoneum (abdomen). While its precise normal biological function is not fully understood, it may play a role in cell adhesion. Research involving mesothelin knockout mice indicated that the protein is not essential for normal growth or reproduction.
Mesothelin’s Role in Cancer Development
Mesothelin’s presence becomes significantly elevated in several cancers, including malignant mesothelioma, ovarian cancer, pancreatic cancer, and lung adenocarcinoma. This overexpression suggests mesothelin contributes to cancer progression through multiple biological mechanisms. It promotes unchecked cell growth and proliferation in tumor cells, partly by influencing signaling pathways such as NF-κB, STAT3, and PI3K/Akt. Activation of these pathways can lead to increased production of molecules like interleukin-6 (IL-6), which further supports cancer cell survival and growth.
Mesothelin is also implicated in preventing programmed cell death, known as apoptosis, in cancer cells. It can stimulate Akt phosphorylation, promoting anti-apoptotic genes while inhibiting pro-apoptotic factors. This allows cancer cells to evade the natural processes that would normally eliminate damaged or abnormal cells. Mesothelin also contributes to the spread of cancer cells, a process called metastasis. It has been shown to interact with MUC16 (also known as CA125), a protein expressed on the surface of many tumor cells, facilitating cell adhesion and peritoneal implantation, especially in ovarian cancer.
Beyond promoting growth and spread, mesothelin can also contribute to drug resistance in cancer cells. Its expression has been linked to increased resistance to certain chemotherapy drugs, including TNF-α, paclitaxel, and combinations of platinum and cyclophosphamide. This resistance can occur through mechanisms involving the MAPK/ERK signaling pathway, which helps cancer cells survive drug-induced stress. The overexpression of mesothelin can trigger epithelial-to-mesenchymal transition (EMT), an early step in tumor invasion and metastasis.
Detecting Cancer with Mesothelin
Mesothelin serves as a valuable biomarker for detecting and monitoring certain cancers. Mesothelin can be shed from the surface of tumor cells into the bloodstream and other bodily fluids. This shedding makes it detectable through blood tests, typically using ELISA assays, providing a non-invasive method for assessment.
The levels of soluble mesothelin-related proteins (SMRPs), which are derivatives of mesothelin, are often elevated in the blood of patients with malignant mesothelioma and ovarian cancer. This makes SMRPs a useful tool for diagnosis, particularly for mesothelioma, where the MESOMARK® test is an FDA-approved blood test for managing the disease. While mesothelin has high specificity (around 96%) as a diagnostic marker for mesothelioma, its sensitivity can vary, sometimes as low as 47% in certain studies, though other analyses report sensitivities between 60-90%.
Monitoring mesothelin levels can also help track disease progression and assess a patient’s response to treatment. Changes in serum mesothelin concentrations can indicate whether a tumor is growing or shrinking, providing insights into the effectiveness of therapies. Although its utility as a prognostic indicator has shown mixed results in studies for mesothelioma, it can be a useful marker in combination with other factors. For pancreatic cancer, while mesothelin is overexpressed in tumor tissue, its levels in the bloodstream do not always correlate with tumor burden or changes in response to treatment, possibly due to shed mesothelin being trapped within the tumor microenvironment.
Targeting Mesothelin for Cancer Treatment
The high and specific expression of mesothelin on the surface of many cancer cells, combined with its limited presence in healthy tissues, makes it an attractive target for various cancer therapies. One promising approach involves antibody-drug conjugates (ADCs). These engineered molecules combine an antibody that specifically binds to mesothelin with a potent chemotherapy drug. Once the ADC attaches to a mesothelin-expressing cancer cell, the drug is released inside the cell, delivering a targeted payload.
Examples of ADCs targeting mesothelin include anetumab ravtansine, which delivers a tubulin inhibitor, and other experimental ADCs that induce pyroptosis, programmed cell death, in cancer cells. Clinical trials are actively investigating several mesothelin-targeting ADCs for cancers like mesothelioma and lung cancer, aiming to evaluate their safety and effectiveness. Early results for some ADCs suggest they may slow tumor growth, and combining them with immunotherapies like Opdivo has shown longer progression-free survival in some patients with advanced solid tumors.
Another therapeutic strategy utilizes immunotoxins, which are proteins that combine an antibody fragment binding to mesothelin with a bacterial toxin. These immunotoxins, such as LMB-100 (formerly SS1P), are designed to selectively deliver the toxin to mesothelin-expressing cancer cells, leading to their death. While promising results have been observed in clinical trials, a challenge with immunotoxins can be the development of anti-drug antibodies by patients, which can reduce the effectiveness of subsequent doses.
Chimeric Antigen Receptor (CAR) T-cell therapy represents an advanced form of immunotherapy where a patient’s T-cells are genetically engineered to recognize and attack mesothelin-positive cancer cells. These engineered CAR T-cells are designed with a synthetic receptor that binds directly to mesothelin, triggering the T-cell to destroy the cancer. Clinical trials are exploring the use of mesothelin-targeted CAR T-cells, sometimes in combination with other immunotherapies like PD-1 blockade agents, for malignant pleural diseases, including mesothelioma and metastatic lung or breast cancers. While CAR T-cell therapy has shown significant success in blood cancers, its application in solid tumors is more challenging due to factors like heterogeneous antigen expression and the immunosuppressive tumor microenvironment.