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 currently conducting a Phase I clinical trial of the anti-mesothelin immunotoxin SS1P in patients with mesothelin expressing cancers. A total of 31 patients (10 peritoneal mesothelioma; 6 pleural mesothelioma; 1 inguinal mesothelioma; 12 ovarian cancer; 2 pancreatic cancer) have been treated to date. The maximum tolerated dose of SS1P given intravenously every other day x 3 doses is 45 micrograms/kg/dose. To prevent pleuritis that was the dose limiting toxicity at higher doses of SS1P, we will be pre-treating patients with prednisone to determine if this will allow further dose escalation. Of the 30 evaluable patients treated, 15 had stable disease; 2 had minor response; 2 had resolution of ascites and 11 had progressive disease. One patient with ovarian cancer had complete resolution of abdominal and pelvic ascites lasting 6 months; 1 patient with peritoneal mesothelioma has had complete resolution of abdominal ascites lasting more than 3 years. We are currently planning phase II clinical trials of SS1P for patients with malignant mesothelioma and other mesothelin expressing malignancies.? ? 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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