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的5%，是癌症死亡的第四大原因。根据SEER癌症统计审查，估计2009年将有超过42，000例胰腺癌新发病例和超过35，000例死亡。目前的治疗方案受益有限，诊断后的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率。很明显，需要更有效的治疗胰腺癌的疗法。 超声强化药物传递是一个活跃而有前途的研究领域。超声已被证明可以增强血管渗透性和药物渗透到组织中，主要是由于与空化相关的机制。正在进行的研究工作（包括本提案中提出的我们实验室的初步数据）已经确定了可能在体内有效的超声机制和参数。已经在各种异种移植物和同基因自体移植物动物模型中进行了几项体内研究，这些研究已经证明超声增强药物递送在减小肿瘤大小和增加存活时间方面是有效的;然而，这些肿瘤模型，特别是胰腺癌，已经被批评为不切实际并且不能代表在人类疾病中看到的真实体内环境。 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，但也是快速翻译。该方案中的策略的吸引力在于，它利用了作为当前护理标准（吉西他滨）的化疗剂，沿着聚焦超声技术，该技术目前可用且易于实施，以将这些结果快速转化为人体临床试验。此外，它首次为超声增强药物递送的研究带来了独特而逼真的动物模型（KPC小鼠），这将为评估临床转化的潜力提供更真实的数据。该提案的总体目标是研究超声是否可以增强靶向药物渗透到体内胰腺肿瘤中并改善生存期。我们相信，成功实现这一提案的具体目标将是将这种有前途的方法应用于胰腺癌患者的重要一步。

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.