Targeted Therapy of Mesothelioma and Development of Bloo

我们的临床研究集中在表达间皮素的癌症的靶向治疗。间皮素是一种40 kDa的细胞表面糖蛋白，存在于胸膜、心包和腹膜衬里的正常间皮细胞上。它在间皮瘤、卵巢癌和胰腺癌患者中高度表达。我们正在NCI进行抗间皮素免疫毒素SS 1 P的临床试验。在I期试验中，我们治疗了34例患者（20例间皮瘤; 12例卵巢癌; 2例胰腺癌），并在几例患者中观察到抗肿瘤活性。基于这些结果，我们即将开始在间皮瘤患者中进行SS 1 P的II期临床试验。由于我们的实验室研究显示SS 1 P和化疗之间有显著的协同作用，因此II期研究将评估SS 1 P与化疗联合的活性。我们还正在进行MORAb-009的I期临床试验，MORAb-009是一种靶向间皮素的人源化单克隆抗体。间皮瘤以及其他表达间皮素的癌症患者正在接受治疗。除了利用间皮素作为癌症治疗的靶标之外，我们正在评估血清间皮素作为表达间皮素的肿瘤的肿瘤标志物。与LMB的其他成员以及实验室医学系的Alan Remaley博士合作，我们开发了一种ELISA来测量血清间皮素。我们的研究结果表明，间皮瘤和卵巢癌患者中的大多数间皮素水平升高。我们的研究结果还表明，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，血清间皮素可以是一个有价值的肿瘤标志物，以跟踪和监测患者的肿瘤表达间皮素的治疗反应。我们将使用这种ELISA来测量胸膜间皮瘤患者的血清间皮素水平，该患者正在接受组蛋白去乙酰化酶抑制剂SAHA的III期、随机、双盲、安慰剂对照试验。这项多机构试验由默克公司进行。预计将增加660例患者，这将使我们能够确定间皮素作为间皮瘤肿瘤标志物的效用。血清间皮素水平将与肿瘤分期、肿瘤负荷和组织学以及对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.