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

• 批准号: 7319771
• 负责人: DUXIN SUN
• 金额: $ 28.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/7319771
• 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; Class; 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; Localized; 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; Rate; Recurrence; Recurrent disease; Regulation; Research Personnel; Resectable; Resistance; Site; Standards of Weights and Measures; Surgeon; Surgical margins; Survival Rate; System; TAG-72 Antigen; Therapeutic; Therapeutic Effect; Time; Toxic effect; Treatment Protocols; Unresectable; Xenograft procedure; analog; antibody conjugate; anticancer activity; antigen binding; base; cancer therapy; chemotherapy; clinical application; experience; falls; gamma-A; glycosylation; improved; in vivo; lymph nodes; metastatic colorectal; novel; novel therapeutics; pharmacokinetic model; programs; protein degradation; research clinical testing; response; therapeutic target; tumor

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疗是结直肠癌最常见和最有效的治疗方法。然而，即使在假定可切除的癌症患者中，未被识别的隐匿性疾病的威胁仍然是外科医生的主要挑战。因此，40%的患者最终发展为复发或转移性疾病。远处转移患者的长期生存率低于10%，迄今为止，还没有可靠的系统为外科医生提供实时术中信息，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，超过一半的复发性结直肠癌患者由于肿瘤的关键位置而不能接受手术治疗。对于这些复发性结直肠癌患者，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具有多种遗传异常，针对特定癌基因的单一药物不太可能完全有效。格尔德霉素（geldanamycin，GA）及其类似物通过抑制分子伴侣Hsp 90同时下调多个癌基因的表达，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价，并且需要新的修饰或药物递送方法用于未来的临床应用。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结直肠癌提供治疗方案。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（HuCC 49 ACH 2）-糖苷酶偶联物将靶向参与疾病过程的肉眼肿瘤、隐匿性肿瘤和淋巴结，并将用于放射免疫导向手术（RIGS），以准确评估切除边缘并最终提高患者生存率。在手术不可能的情况下，我们将利用肿瘤定位的抗体-酶缀合物在肿瘤中位点特异性激活格尔德霉素前药。我们假设GA前药的位点特异性活化将增加肿瘤中的局部活性药物浓度，从而改善其抗癌功效，而前药将在正常组织中保持无活性（由于缺乏抗体-酶缀合物），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活化。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。具体目标三：利用肿瘤定位抗体酶（AbE）对格尔德霉素前体药物（GA前体药物）进行位点特异性激活，以提高其药效，降低其毒副作用。总之，这种集成系统提供了强大的临床应用，以彻底改变外科手术，并为晚期化疗耐药结直肠癌提供了新的靶向药物治疗。