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：
7596342
负责人：
DUXIN SUN
金额：
$ 28.11万
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/7596342
关键词：
17-(Allylamino)-17-demethoxygeldanamycin 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin Adjuvant Chemotherapy Adverse effects Animal Model Antibodies Binding CC49 antibody Cancer Etiology Cancer Patient Cessation of life Client Colorectal Cancer Data Detection Disease Distant Metastasis Drug Delivery Systems Enzymes Excision Figs - dietary Future Galactose Galactosidase Geldanamycin Glycoside Hydrolases Goals Hypoxia Image Imaging Techniques In Vitro Knowledge Label Location Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of pancreas Methods Modeling Modification Molecular Abnormality Molecular Chaperones Monitor Monoclonal Antibody CC49 Normal tissue morphology Oncogenes Operative Surgical Procedures Patients Pharmaceutical Preparations Pharmacotherapy Phase I Clinical Trials Phase II Clinical Trials Physiological Positron-Emission Tomography Postoperative Period Principal Investigator Process Prodrugs Property Proteins Radiation therapy Radio Radioimmunoguided Surgery Recurrence Recurrent disease Regulation Research Personnel Resectable Resistance Site Surgeon Surgical margins Survival Rate System TAG-72 Antigen The Sun Therapeutic Therapeutic Effect Time Toxic effect Treatment Protocols Unresectable Xenograft procedure analog antibody conjugate anticancer activity antigen binding base cancer therapy chemotherapy clinical application effective therapy experience falls gamma-A glycosylation improved in vivo lymph nodes metastatic colorectal new therapeutic target novel novel therapeutics pharmacokinetic model 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）：结直肠癌是癌症死亡的第三大常见原因。手术结合辅助化疗和放射治疗是结直肠癌最常见、最有效的治疗方法。然而，即使在假定患有可切除癌症的患者中，未被识别的隐性疾病的威胁仍然是外科医生面临的重大挑战。因此，40%的患者最终会出现复发或转移性疾病。对于有远处转移的患者，长期生存率降至10%以下。迄今为止，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，以准确预测切除的充分性（包括手术切缘和隐匿性疾病））。然而，超过一半的结直肠癌复发患者由于肿瘤位置关键而无法接受手术治疗。对于这些复发性结直肠癌患者，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基因异常，针对特定癌基因的单一药物不太可能完全有效。对此，格尔德霉素（GA）及其类似物通过抑制分子伴侣Hsp90同时下调多种癌基因，为晚期结直肠癌的治疗提供了希望。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药物递送方法。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，并为不可切除和晚期化疗耐药的结直肠癌提供治疗方案。长期目标是将手术中的肿瘤检测和靶向药物治疗整合到具有相同肿瘤靶向抗体的一个系统中。我们假设抗TAG-72抗体（HuCC49ACH2）-糖苷酶缀合物将靶向参与疾病过程的肉眼肿瘤、隐匿性肿瘤和淋巴结，并将用于放射免疫引导手术（RIGS）以准确评估切除边缘和最终提高患者的生存率。在无法进行手术的情况下，我们将利用肿瘤定位的抗体-酶缀合物来对肿瘤中的格尔德霉素前药进行位点特异性激活。我们假设 GA 前药的位点特异性激活将增加肿瘤中的局部活性药物浓度，从而提高其抗癌功效，而前药将在正常组织中保持非活性（由于缺乏抗体-酶缀合物），从而降低其抗癌功效。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-半乳糖苷酶缀合物 (AbE) 递送至结直肠癌，用于手术中的肿瘤检测和未来的前药激活。具体目标二：合成具有肿瘤酶特异性激活特性的格尔德霉素-半乳糖前药（GA-前药）。具体目标三：通过肿瘤定位的抗体酶（AbE）对格尔德霉素前药（GA前药）进行位点特异性激活，以提高其疗效并减少其副作用。总之，该集成系统提供了强大的临床应用，可以彻底改变外科手术，并为晚期化疗耐药结直肠癌提供新的靶向药物治疗。