Our clinical research is focused on targeted therapy of mesothelin expressing cancers. Mesothelin is a 40-kDa cell surface glycoprotein that is present on normal mesothelial cells lining the pleura, pericardium and peritoneum. It is highly expressed in patients with mesothelioma and ovarian and pancreatic cancers. We are conducting clinical trails of the anti-mesothelin immunotoxin SS1P at the NCI. In the Phase I trial we treated 34 patients (20 mesothelioma; 12 ovarian cancer; 2 pancreatic cancer) and anti-tumor activity was noted in several patients. Based on these results we are about to start a Phase II clinical trial of SS1P in patients with mesothelioma. Since our laboratory studies show marked synergy between SS1P and chemotherapy this phase II study will evaluate the activity of SS1P in combination with chemotherapy. We are also conducting a phase I clinical trial of MORAb-009, a humanized monoclonal antibody targeting mesothelin. Patients with mesothelioma as well as other cancers that express mesothelin are being treated. In addition to utilizing mesothelin as a target for cancer therapy we are evaluating serum mesothelin as a tumor marker for mesothelin expressing tumors. In collaboration with other members of the LMB, as well as Dr. Alan Remaley of the Department of Laboratory Medicine we have developed an ELISA to measure serum mesothelin. Our results show that mesothelin levels are elevated in majority of patients with mesothelioma and ovarian cancer. Our results also show that serum mesothelin levels fall after surgery in patients with peritoneal mesothelioma. These results suggest that serum mesothelin can be a valuable tumor marker to follow and monitor treatment response in patients whose tumors express mesothelin. We will use this ELISA to measure serum mesothelin levels in patients with pleural mesothelioma being treated on a Phase III, randomized, double-blind, placebo-controlled trial of the histone deacetylase inhibitor SAHA. This multi-institutional trial being conducted by Merck Inc. and expected to accrue 660 patients will allow us to determine the utility of mesothelin as a tumor marker in mesothelioma. Serum mesothelin levels will be correlated with tumor stage, tumor burden, and histology as well as response to SAHA.
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