Ultrasound enhanced penetration for treatment of pancreatic cancer

描述（由申请人提供）：胰腺癌占美国癌症死亡人数的5%，是癌症死亡的第四大原因。根据SEER癌症统计评论，估计2009年将有超过42,000例新的胰腺癌病例和超过35,000例死亡。目前的治疗方案获益有限，诊断后5年生存率低于5%。目前的标准治疗，吉西他滨，只能提高几周的生存期。很明显，需要更有效的治疗胰腺癌的方法。超声增强给药是一个活跃和有前途的研究领域。超声已被证明可以增强血管通透性和药物对组织的渗透，主要是由于与空化有关的机制。正在进行的研究工作（包括本提案中我们实验室提供的初步数据）已经确定了可能在体内有效的超声机制和参数。在各种异种移植物和同种自体移植物动物模型中进行的几项体内研究表明，超声增强药物输送在减小肿瘤大小和增加生存时间方面是有效的；然而，这些肿瘤模型，特别是胰腺癌的模型，被批评为不现实，不能代表人类疾病中真实的体内环境。在这个提案中，我们相信我们已经开发了一项研究，包括严格的基础科学，但也可以快速翻译。该提案中策略的吸引力在于，它利用了目前标准的化疗药物（吉西他滨）以及目前可用且易于实施的聚焦超声技术，以快速将这些结果转化为人体临床试验。此外，它首次为超声增强给药研究带来了一种独特而真实的动物模型（KPC小鼠），这将为评估临床转化的潜力提供更真实的数据。本提案的总体目的是研究超声是否可以增强靶向药物对体内胰腺肿瘤的渗透并提高生存时间。我们相信，该提案的具体目标的成功实现将是将这种有希望的方法应用于患有胰腺癌的人类患者的重要一步。

DESCRIPTION (provided by applicant): Pancreatic cancer accounts for 5% of cancer deaths in the United States and is the fourth leading cause of cancer mortality. According to the SEER Cancer Statistics Review, it is estimated that in 2009 there will have been over 42,000 new cases of pancreatic cancer and over 35,000 deaths. Current treatment options are of limited benefit with a 5-year survival rate following diagnosis of less than 5%. The current standard-of-care therapy, gemcitabine, only improves survival by a few weeks. It is clear that more effective therapy for the treatment of pancreatic cancer is needed. Ultrasound-enhanced drug delivery is an active and promising area of research. Ultrasound has been demonstrated to enhance vascular permeability and drug penetration into tissue, primarily due to mechanisms related to cavitation. Ongoing research efforts (including preliminary data from our lab presented in this proposal) have identified ultrasound mechanism and parameters that are likely to be effective in vivo. Several in vivo studies have been performed in various xenograft and syngenic autograft animal models that have demonstrated that ultrasound enhanced drug delivery is effective in decreasing tumor size and increasing survival duration; however, these tumor models, especially for pancreatic cancer, have been criticized for being unrealistic and not representative of the true in vivo environment seen in the human disease. In this proposal, we believe that we have developed a study that includes rigorous fundamental science, but also is rapidly translatable. The attractiveness of the strategy in this proposal is that it utilizes a chemotherapeutic agent that is the current standard of care (gemcitabine) along with focused ultrasound technology that is currently available and readily implementable to rapidly translate these results into human clinical trials. In addition, it brings for the first time to the study of ultrasound-enhanced drug delivery a unique and realistic animal model (KPC mice), which will provide much more realistic data to evaluate the potential for clinical translation. The overall aim of this proposal is to investigate whether ultrasound can enhance targeted drug penetration into an in vivo pancreatic tumor and improve survival duration. We believe that the successful accomplishment of the specific aims of this proposal will be a major step toward applying this promising approach to human patients who are suffering from pancreatic cancer.