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

肿瘤检测和癌症靶向药物治疗的集成系统

基本信息

批准号：
7662058
负责人：
DUXIN SUN
金额：
$ 22.59万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7662058
关键词：
17-(Allylamino)-17-demethoxygeldanamycin 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin Adjuvant Chemotherapy Adverse effects Antibodies Binding Cancer Etiology Cancer Patient Cessation of life Client Colorectal Colorectal Cancer Data Deposition Detection Disease Distant Metastasis Drug Delivery Systems Enzymes Excision Figs - dietary Future Galactose Galactosidase Geldanamycin Glycoside Hydrolases Goals Hypoxia Image Lead Link Localized Location Malignant Neoplasms Malignant neoplasm of pancreas Metastatic/Recurrent Disease Methods Microscopic Modality Modification Molecular Abnormality Molecular Chaperones Normal tissue morphology Oncogenes Operative Surgical Procedures Patients Pharmaceutical Preparations Pharmacotherapy Process Prodrugs Property Radiation therapy Radioimmunoconjugate Radioimmunoguided Surgery Rate Recurrence Recurrent disease Research Personnel Resectable Resistance Site Staging Standards of Weights and Measures Surgeon Surgical margins Survival Rate System TAG-72 Antigen Therapeutic Time Toxic effect Treatment Protocols Tumor Tissue Unresectable analog anticancer activity chemotherapy clinical application falls gamma-A glycosylation improved lymph nodes neoplastic cell novel therapeutics pancreatic neoplasm programs protein degradation research clinical testing response tumor

项目摘要

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.

描述（由申请人提供）：大肠癌是癌症死亡的第三大原因。手术与辅助化疗和放射疗法结合使用，是结直肠癌的最常见和有效治疗方法。但是，即使在假定可切除癌症的患者中，对外科医生的神秘疾病的威胁仍然是一个主要的挑战。因此，40％的患者最终患有复发或转移性疾病。在具有远处转移的患者中，长期存活率降至10％以下。到期，尚未开发出可靠的系统来为外科医生提供实时的术中信息，以准确预测切除的适当性（手术缘和神秘疾病）。然而，由于肿瘤的关键位置，超过一半的结直肠癌患者无法接受手术程序。对于这些复发性结肠直肠癌的患者，标准化疗的缓解率为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具有多种遗传异常，靶向特定癌基因的一种药物不太可能完全有效。在这方面，Geldanamycin（GA）及其类似物通过抑制分子伴侣HSP90来同时下调许多癌基因，从而为治疗晚期结直肠癌提供了希望。但是，它们的严重毒性限制了他们的临床评估，并且需要新的修改或药物输送方法来进行未来的临床应用。因此，我们打算开发一种用于神秘肿瘤和异常淋巴结的术中实时检测系统的系统，并为无法切除和晚期化学抗性的结直肠癌提供治疗方案。长期目标是将术中肿瘤检测进行手术和靶向药物治疗纳入具有相同肿瘤靶向抗体的系统。我们假设抗TAG-72抗体（HUCC49ACH2） - 糖苷酶结合物将针对疾病过程中涉及的总肿瘤，隐匿性肿瘤和淋巴结，并将用于放射性免疫性手术（RIGS），以准确评估切除率和最终患者的生存。如果不可能进行手术，我们将利用肿瘤 - 定位的抗体 - 酶结合物来用于肿瘤中Geldanamycin前药的位点特异性激活。我们假设GA前药的位点特异性激活将增加肿瘤中局部活性药物浓度，从而提高其抗癌功效，而该前药将在正常组织中保持不活跃（由于缺乏抗体 - 酶结合物）并从而降低了其副作用。该项目中提出了三个特定的目标：具体目的I：送达抗TAG-72抗体 - 半乳糖苷酶结合物（ABE），以进行大肠癌，以在手术和将来的前药激活中进行肿瘤检测。具体目标II：合成肿瘤中酶具有酶特异性激活特性的Geldanamycin-半乳糖前药（GA-产物）。特定的目标III：特定于肿瘤 - 定位抗体 - 酶（ABE）的位点特异性激活Geldanamycin前药（GA前药），以提高其功效并降低其副作用。总而言之，该集成系统提供了强大的临床应用，可以彻底改变手术程序，并为晚期化学抗性的结直肠癌提供了新的靶向药物治疗。