Ultrasound-guided gene delivery in pancreatic cancer

超声引导的胰腺癌基因递送

• 批准号: 7913010
• 负责人: Pier Paolo Claudio
• 金额: $ 7.1万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913010
• 关键词: Achievement; Address; Adenoviruses; Advanced Malignant Neoplasm; Affect; Animal Model; Animals; Apoptosis; Biological; Cancer Etiology; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Contrast Media; Development; Diagnostic; Disease; Distant; Drug usage; Early Diagnosis; Excision; Future; Gases; Gene Delivery; Genes; Genetic; Growth; Human; Immune; Immune system; Immunocompromised Host; Incidence; Injection of therapeutic agent; Interferons; K-ras Oncogene; MADH4 gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Microbubbles; Microbubbles Ultrasound Contrast Medium; Microspheres; Modification; Mutation; Nanosphere; Neoplasms; Normal Cell; Nucleic Acids; Nude Mice; Oncogene Activation; Operative Surgical Procedures; Pancreatic carcinoma; Patients; Permeability; Phase I Clinical Trials; Property; Radiation; Radiation therapy; Research; Resectable; Resistance; Shock; Specificity; Staging; Systemic Therapy; TP53 gene; Testing; Therapeutic; Tissues; Transducers; Translations; Tumor Suppressor Genes; Tumor-Suppressor Gene Inactivation; Ultrasonic wave; Ultrasonography; United States; Viral; Viral Vector; Virus; Virus Replication; Xenograft procedure; adenovirus mediated delivery; base; cancer cell; cancer therapy; chemotherapy; conventional therapy; cytokine; effective therapy; gene delivery system; gene therapy; macromolecule; mouse model; novel; novel strategies; outcome forecast; pancreatic neoplasm; physical property; prevent; promoter; public health relevance; response; tumor; tumor growth

DESCRIPTION (provided by applicant): At present, no effective therapy is available for metastatic pancreatic cancer. This proposal seeks to overcome this impasse by employing a novel approach employing a cancer-specific conditionally replication competent adenovirus that expresses a therapeutic cytokine, IFN-? or mda-7/IL-24 (a cancer terminator virus (CTV)), in combination with an ultrasound (US) contrast agent and US waves. These studies are based on the observations that IFN-? and mda-7/IL-24 displays selective anti-pancreatic cancer activity, potent 'bystander' anti-tumor activity, anti-angiogenic activity. Based on profound multifunctional, selective anti-cancer activities of mda-7/IL-24, this gene has been evaluated in a Phase I clinical trial in patients with advanced cancers, not including pancreatic cancer, by repeat intratumoral injections with a non-replicating adenovirus (Ad) expressing mda-7/IL-24 (Ad.mda-7; INGN 241). This therapeutic approach was safe and resulted in significant clinical activity. Restrictions of Ad-based therapies include rapid degradation and clearance by the immune system, thus limiting systemic applications. By using US contrast agents (microbubbles) we will achieve both specificity of action as well as protection of the viral vectors from inactivation. Additionally, the gas filled microspheres effectively lower the energy threshold for cavitation allowing diagnostic transducers operating within the energy levels mandated by the FDA to be used for drug/gene delivery. In the sonification zone the microbubbles undergo cavitation, destroying the bubbles and releasing their contents, creating small shockwaves that increase cell permeability. This has been shown to increase transcapillary passage of macromolecules or nanospheres co-delivered by the microbubbles in experimental animals. In principle, the present approach should allow efficient CTV delivery and may evoke a cure in both primary and distant mestastatic pancreatic cancer, which will be tested in immune incompetent animal models. Successful accomplishment of these studies will pave the way for future clinical trials. PUBLIC HEALTH RELEVANCE: The present study seeks to develop an effective therapy for pancreatic cancer that employs cancer-specific apoptosis-inducing cytokines, IFN-? or mda-7/IL-24, delivered by a conditionally replication competent adenovirus, a cancer terminator virus (CTV), in combination with ultrasound contrast agents and ultrasound waves. This novel approach will permit efficient systemic delivery of the CTV to tumors, offering the potential to develop a 'cure' for both localized and metastatic pancreatic cancer. Successful achievement of the objectives of the present proposal will provide for rapid translation into the clinic as a new and potentially effective therapy for metastatic pancreatic cancer.

描述（申请人提供）：目前，转移性胰腺癌尚无有效的治疗方法。该提案试图通过采用一种新方法来克服这一僵局，该方法采用癌症特异性条件复制能力腺病毒，表达治疗性细胞因子 IFN-α。或 mda-7/IL-24（一种癌症终结病毒 (CTV)），与超声波 (US) 造影剂和超声波相结合。这些研究基于 IFN-α 的观察结果。 mda-7/IL-24 显示选择性抗胰腺癌活性、有效的“旁观者”抗肿瘤活性、抗血管生成活性。基于 mda-7/IL-24 的深刻多功能、选择性抗癌活性，该基因已在晚期癌症（不包括胰腺癌）患者的 I 期临床试验中进行了评估，方法是通过重复瘤内注射表达 mda-7/IL-24 的非复制腺病毒 (Ad)（Ad.mda-7；INGN 241）。这种治疗方法是安全的并且产生了显着的临床活性。基于 Ad 的疗法的限制包括免疫系统的快速降解和清除，从而限制了系统应用。通过使用美国造影剂（微泡），我们将实现作用的特异性以及保护病毒载体免于失活。此外，充气微球有效降低了空化的能量阈值，允许诊断传感器在 FDA 规定的能量水平内运行，用于药物/基因输送。在超声处理区，微泡发生空化，破坏气泡并释放其内容物，产生小的冲击波，增加细胞的渗透性。这已被证明可以增加实验动物中微泡共同递送的大分子或纳米球的跨毛细血管通过。原则上，目前的方法应该允许有效的 CTV 递送，并可能治愈原发性和远处转移性胰腺癌，这将在免疫功能低下的动物模型中进行测试。这些研究的成功完成将为未来的临床试验铺平道路。公共健康相关性：本研究旨在开发一种有效的胰腺癌疗法，该疗法采用癌症特异性细胞凋亡诱导细胞因子 IFN-α。或 mda-7/IL-24，由有条件复制能力的腺病毒（一种癌症终止病毒 (CTV)）与超声造影剂和超声波结合递送。这种新颖的方法将允许将 CTV 有效地全身输送到肿瘤，从而为开发局部和转移性胰腺癌的“治愈方法”提供了潜力。本提案目标的成功实现将作为转移性胰腺癌的一种新的且潜在有效的疗法快速转化为临床。