Targeted therapy of mesothelin expressing cancers using

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。我们目前正在进行抗间皮素免疫毒素SS 1 P在表达间皮素的癌症患者中的I期临床试验。迄今为止，共治疗了31例患者（10例腹膜间皮瘤; 6例胸膜间皮瘤; 1例腹股沟间皮瘤; 12例卵巢癌; 2例胰腺癌）。每隔一天静脉给药3次的SS 1 P最大耐受剂量为45 μ g/kg/剂。为了预防胸膜炎，这是在较高剂量的SS 1 P的剂量限制性毒性，我们将用泼尼松预治疗患者，以确定这是否允许进一步剂量递增。在接受治疗的30例可评价患者中，15例疾病稳定; 2例轻微缓解; 2例腹水消退，11例疾病进展。1例卵巢癌患者腹腔和盆腔腹水完全消退，持续6个月; 1例腹膜间皮瘤患者腹腔腹水完全消退，持续3年以上。我们目前正在计划对恶性间皮瘤和其他表达间皮素的恶性肿瘤患者进行SS 1 P的II期临床试验。 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 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.