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The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
CA-125 is thought to help the growth of tumors by suppressing the response of natural killer cells, thereby protecting cancer cells from an immune response. CA-125 is also thought to participate in cell-to-cell interactions that enable metastasis. This is supported by evidence showing that CA-125 binds selectively to mesothelin, a glycoprotein normally expressed by the mesothelial cells of the peritoneum (the lining of the abdominal cavity). CA-125/mesothelin interactions are thought to represent the first step in tumor cell invasion of the peritoneum. Overexpression of CA-125 has also been associated with drug resistance as it can protect tumor cells from the effects of cytotoxic agents such as cisplatin. CA-125 is also a component of the ocular surface (including the cornea and conjunctiva), the respiratory tract and the female reproductive tract epithelia. In this case, its high degree of glycosylation creates a hydrophilic environment that acts as a lubricating barrier against foreign particles and infectious agents on the apical membrane of epithelial cells.
Malignant Pleural Mesothelioma
Published in Dongyou Liu, Tumors and Cancers, 2017
Raúl Barrera-Rodríguez, Carlos Pérez-Guzmán
Serology: Serum mesothelin-related protein (SMRP) is elevated in >60% of patients with MPM and <2% of patients with other pleural or lung disease. Another biomarker, fibulin-3, identifies mesothelioma with a sensitivity of 72.9%–96.7% and a specificity of 88.5%–95.5%. Overall, SMRP gives a better diagnostic accuracy than fibulin-3 when measured in plasma or pleural fluid.
Asbestos exposure and mesothelioma
Published in Dorsett D. Smith, The Health Effects of Asbestos, 2015
The results of the treatment of mesotheliomas have generally been poor. Great efforts have been made to make an early diagnosis with the hope that early treatment will extend life expectancy. A variety of serum markers have been used for diagnostic and prognostic purposes, but not enough information is available to recommend their use routinely. (Tabata C, Shibata E, Tabata R et al. Serum HMGB1 as a prognostic marker for malignant pleural mesothelioma. BMC Cancer 2013;13:205; Hollevoet K, Reitsma JB, Creaney J et al. Serum mesothelin for diagnosing malignant pleural mesothelioma: An individual patient data metaanalysis. J Clin Oncol 2012;30(13):1541–9; Creaney J, Sneddon S, Dick IM et al. Comparison of the diagnostic accuracy of the MSLN gene products, mesothelin and megakaryocyte potentiating factor, as biomarkers for mesothelioma in pleural effusions and serum. Dis Markers 2013;35(2):119–27.)
Barriers and Opportunities for CAR T-Cell Targeting of Solid Tumors
Published in Immunological Investigations, 2022
Jose R. Conejo-Garcia, Jose A. Guevara-Patino
The paucity of specific targets accessible on the tumor cell surface has led to an array of CAR T-cell interventions against targets such as mesothelin, despite expression in vital tissues, such as pericardium, pleura or the peritoneal lining. Mesothelin is overexpressed in ovarian, pancreatic and lung cancer, among other tumors. Despite broad expression beyond tumor cells, regional delivery of CAR T-cell therapy can theoretically provide a layer of safety, according to a recent clinical trial (Adusumilli et al. 2021). These interventions allowed combination with Pembrolizumab and demonstrated some antitumor efficacy in patients with malignant pleural diseases. However, after the publication of the results of this initial trial, a dose-escalation CAR T-cell trial in patients with mesothelioma at the same institution (NCT04577326) had to be put on hold, following a patient death. These results underscore the potential of fine-tuned CAR T cells targeting antigens overexpressed in cancer, even if they are also expressed in vital tissues. However, they also evidence the limitations and risks of shared targets, for which “super-T-cells” engineered to overcome tumor-induced immunosuppression would likely result in fatal toxicities.
Recent progress in antibody-based therapeutics for triple-negative breast cancer
Published in Expert Opinion on Drug Delivery, 2022
Wen-Jing Ning, Xue Liu, Hong-Ye Zeng, Zhi-Qiang an, Wen-Xin Luo, Ning-Shao Xia
The current status of BiTE treatment in TNBC is summarized in Table 3. There are currently two clinical trials. The TROP2 and EGFR targets are the most popular. In addition to BiTEs, there are also preliminary studies of bispecific killer cell engagers (BiKEs) in TNBC. Mesothelin is expressed in 30–70% of TNBC patients, and its expression is restricted to healthy tissues [117]. MesobsFab is a BIKE that simultaneously targets mesothelin and CD16. In mesothelin-positive TNBC-PDX NSG mice, MesobsFab can significantly inhibit tumour growth by inducing the ADCC effect, and there is no obvious off-target toxicity [118]. Due to their natural structural advantages, BiTEs and BiKEs can recruit immune cells to kill tumours. They are very promising therapeutic agents and warrant further research in the field of TNBC.
Novel mesothelin antibody-drug conjugates: current evidence and future role in the treatment of ovarian cancer
Published in Expert Opinion on Biological Therapy, 2021
Dennis Mauricio, Justin Harold, Joan R. Tymon-Rosario, Burak Zeybek, Alessandro D. Santin
Ovarian cancer is commonly diagnosed at an advanced stage (i.e. Stages III–IV), and primary treatment consists of surgical debulking and platinum-based chemotherapy, either in an adjuvant or neoadjuvant setting. Although most ovarian cancer patients initially respond to the combination of surgery and chemotherapy, the large majority eventually develop recurrence and inevitably acquire resistance to chemotherapy treatment. The development of novel treatment strategies for platinum-resistant disease remains an unmet medical need. Anti-mesothelin ADCs may offer a novel approach for the treatment of chemotherapy-resistant ovarian tumors. Consistent with this view, there is a wealth of preclinical data supporting their use in multiple tumors, particularly ovarian cancer. These preclinical studies have demonstrated not only a differential expression of mesothelin when compared to normal tissues in multiple difficult to treat human cancers but also efficacy in terms of cell-specific killing as well as ‘bystander effect’ killing. Importantly, recent clinical trials with anetumab ravtansine have demonstrated encouraging clinical activity and tolerability of ADC therapy against multiple mesothelin overexpressing human cancers including ovarian cancer [6].