Targeted Therapy of Mesothelioma and Development of Bloo

我们的临床研究重点是靶向治疗表达间充质蛋白的癌症。间皮蛋白是一种40 kDa的细胞表面糖蛋白，存在于胸膜、心包和腹膜内的正常间皮细胞上。它在间皮瘤、卵巢癌和胰腺癌患者中高度表达。我们正在NCI进行抗间皮蛋白免疫毒素SS1P的临床试验。在I期试验中，我们治疗了34名患者(20名间皮瘤，12名卵巢癌，2名胰腺癌)，并在几名患者中观察到了抗肿瘤活性。基于这些结果，我们即将开始SS1P在间皮瘤患者中的第二阶段临床试验。由于我们的实验室研究显示SS1P与化疗有显着的协同作用，这项II期研究将结合化疗评估SS1P的活性。我们还在进行MORAb-009的I期临床试验，MORAb-009是一种针对间硫蛋白的人源化单抗。间皮瘤患者以及其他表达间皮蛋白的癌症患者正在接受治疗。除了利用间充质蛋白作为癌症治疗的靶点外，我们还在评估血清间充质蛋白作为表达间充质蛋白肿瘤的肿瘤标志物的作用。在与LMB的其他成员以及实验室医学部的Alan Remaley博士的合作下，我们已经开发出一种用于测量血清间皮蛋白的ELISA。我们的结果显示，在大多数间皮瘤和卵巢癌患者中，间皮蛋白水平升高。我们的结果还表明，腹膜间皮瘤患者手术后血清间皮素水平下降。这些结果表明，血清间皮质素可以作为一种有价值的肿瘤标记物，用于跟踪和监测肿瘤表达间皮质素的患者的治疗反应。我们将使用这种酶联免疫吸附试验来检测正在接受组蛋白去乙酰酶抑制剂SAHA的III期随机、双盲、安慰剂对照试验的胸膜间皮瘤患者的血清间皮素水平。这项由默克公司进行的多机构试验，预计将有660名患者参加，这将使我们能够确定间皮林作为间皮瘤的肿瘤标志物的效用。血清间皮蛋白水平将与肿瘤分期、肿瘤负担、组织学以及对SAHA的反应相关。

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.