An integrated system for tumor detection and targeted drug therapy of cancer

简介(申请人提供)：结直肠癌是导致癌症死亡的第三大常见原因。手术配合辅助化疗和放射治疗是结直肠癌最常见和最有效的治疗方法。然而，即使在推定为可切除癌症的患者中，未知的隐匿性疾病的威胁仍然是外科医生面临的主要挑战。因此，40%的患者最终会发展为复发或转移性疾病。在远处转移的患者中，长期存活率降至10%以下。到目前为止，还没有开发出可靠的系统来为外科医生提供实时的术中信息来准确预测切除的充分性(包括手术切缘和隐匿性疾病)。然而，超过一半的复发结直肠癌患者由于肿瘤的关键部位而无法接受手术。对于这些复发的结直肠癌患者，标准化疗的有效率为15%至50%，因此需要探索新的治疗方案。考虑到大多数癌症通常都有多种基因异常，针对特定癌基因的单一药物不太可能完全有效。在这方面，格尔达那霉素(GA)及其类似物通过抑制分子伴侣Hsp90同时下调许多癌基因，为治疗晚期结直肠癌提供了希望。然而，它们的严重毒性限制了它们的临床评估，未来的临床应用需要新的修饰或给药方法。因此，我们打算开发一种术中实时检测隐匿性肿瘤和异常淋巴结的系统，并为无法切除和化疗耐药的晚期结直肠癌提供一种治疗方案。长期目标是将手术中肿瘤检测和靶向药物治疗整合到一个具有相同肿瘤靶向抗体的系统中。我们假设，抗TAG-72抗体(HuCC49ACH2)-糖苷酶结合物将针对大体肿瘤、隐匿性肿瘤和参与疾病过程的淋巴结，并将用于放射免疫引导手术(RIGS)，以准确评估切除边缘，最终提高患者的生存率。在不可能进行手术的情况下，我们将利用肿瘤定位的抗体-酶结合物在肿瘤中特异性激活格尔达霉素前体药物。我们推测，GA前药的定点激活将增加肿瘤内局部活性药物的浓度，从而提高其抗癌效果，而前药在正常组织中将保持无活性(由于缺乏抗体-酶结合物)，从而减少其副作用。该项目提出了三个具体目标：具体目标I：将抗TAG-72抗体-半乳糖苷酶结合物(ABE)输送到结直肠癌，用于手术中的肿瘤检测和未来的前药激活。特定目的II：合成具有肿瘤酶特异性激活特性的格尔达霉素-半乳糖前药(GA-前药)。具体目的III：通过肿瘤定位抗体酶(ABE)对格尔达霉素前药(GA前药)进行定点激活，以提高其疗效并减少其副作用。综上所述，这一集成系统为革新外科手术程序提供了强大的临床应用，并为晚期耐药结直肠癌提供了一种新的靶向药物治疗。

DESCRIPTION (provided by applicant): Colorectal cancer is the third most common cause of cancer death. Surgery, in conjunction with adjuvant chemotherapy and radiation therapy, is the most common and effective treatment for colorectal cancer. However, even in patients with presumed resectable cancer, the threat of unrecognized occult disease remains a major challenge for the surgeon. Therefore, 40% of the patients ultimately develop recurrent or metastatic disease. In patients with distant metastases, long-term survival rates fall to below 10%.To date, no reliable systems have been developed to provide the surgeon with real-time intraoperative information to accurately predict the adequacy of resection (both surgical margins and occult disease). More than half of the colorectal cancer patients with recurrent disease, however, cannot undergo surgical procedure due to the tumor's critical location. For these patients with recurrent colorectal cancer, the standard chemotherapy yields a 15% to 50% response rate, so new therapeutic regimens need to be explored. Considering that most cancers generally have multiple genetic abnormalities, a single drug targeting a particular oncogene is unlikely to be completely effective. In this regard, geldanamycin (GA) and its analogs provide a hope for treating the advanced colorectal cancer by inhibiting the molecular chaperone Hsp90 to simultaneously down-regulate many oncogenes. Their severe toxicity, though, has limited their clinical evaluation, and new modifications or drug delivery methods are required for future clinical application. Therefore, we intend to develop a system for intraoperative real-time detection of occult tumors and abnormal lymph nodes, as well as to provide a therapeutic regimen for unresectable and advanced chemo- resistant colorectal cancer. The long term goal is to integrate intraoperative tumor detection for surgery and targeted drug therapy into one system with the same tumor targeting antibody. We hypothesize that the anti-TAG-72 antibody (HuCC49ACH2)-glycosidase conjugate will target gross tumors, occult tumors, and lymph nodes involved in the disease process, and will be used in radioimmunoguided surgery (RIGS) to accurately assess the resection margin and ultimately improve patient survival. In cases where surgery is impossible, we will take advantage of the tumor-localized antibody-enzyme conjugate for site-specific activation of the geldanamycin prodrug in the tumor. We hypothesize that the site-specific activation of GA prodrug will increase the local active drug concentration in the tumor improving its anticancer efficacy, while the prodrug will remain inactive in normal tissue (due to the lack of antibody- enzyme conjugate) and thereby reducing its side effects. Three specific aims are proposed in the project: Specific aim I: To deliver the anti-TAG-72 antibody-galactosidase conjugate (AbE) to colorectal cancer for tumor detection in surgery and for future prodrug activation. Specific aim II: To synthesize geldanamycin-galactose prodrugs (GA-prodrug) with enzyme specific activation properties in tumors. Specific aim III: To site-specifically activate the geldanamycin prodrug (GA prodrug) by the tumor-localized antibody-enzyme (AbE) in order to increase their efficacy and decrease their side effects. In summary, this integrated system offers a strong clinical application to revolutionize the surgical procedure and provides a new targeted drug therapy for advanced chemo-resistant colorectal cancer.