Efficacy and Safety of a Novel, Implantable Drug-eluting Film in Sarcoma

 描述（申请人提供）：局部复发是腹膜后、腹部和盆腔（RAP）肉瘤最常见的失败模式。尽管肉眼完全切除，但由于肿瘤大小和解剖复杂性，手术切缘通常是阳性的，导致5年局部复发率为50%至90%。死亡率是由于局部而不是远端失败，因此，提高生存率的策略必须降低局部失败率。评价围手术期和/或术中外照射放射治疗、单剂量腹腔热化疗和全身化疗的试验未能证明其获益。 我们最近开发了一种新型的、柔性的、组织适形的、生物相容的聚合物膜（Biomacromolecules，2012，13，406-411），其可以在手术中放置在整个肿瘤切除床上以缓慢地局部包裹化疗药物紫杉醇（“Pax-膜”）并杀死残留的肿瘤细胞。当使用时 在我们的复发性肉瘤的小鼠手术模型中，Pax-膜显著增加了局部组织紫杉醇水平，避免了全身毒性，降低了局部复发率，并改善了总存活率而没有愈合并发症（Annals of Surgical Oncology，2012，19，199-206.）。利用保留肿瘤结构和微环境的器官型体外培养方法，能够对给定肿瘤对化疗药物递送的反应进行药效学分析，从而提供预测哪些特定组织学或潜在地哪些特定患者从Pax膜中获益最多的手段。最后，我们建立了能够在手术后快速局部肿瘤复发的小鼠异种移植模型，这使我们能够评估抗肿瘤治疗对各种人肉瘤的体内疗效。有了这些技能和资源，我们现在可以解决以下三个具体目标：具体目标1：研究Pax膜对切除的患者源性肉瘤的体外反应的疗效和药效学特征。 具体目标2：确定Pax膜在体内预防人肉瘤异种移植物局部复发的药效学特征和作用机制。 具体目标3：在临床前大型手术切除动物模型中评估Pax膜植入的安全性、可行性和围手术期发病率。成功完成这一提议将回答这样的假设，即长时间暴露于紫杉醇负载的聚合物膜将：1）降低体外肿瘤细胞活力 对于人源性肉瘤细胞系和患者肿瘤样品，如通过器官型培养评估的; 2）在人肉瘤的小鼠手术模型中降低局部复发率并提高存活率;和3）证明对于局部区域药物递送是安全和可行的，实现高的局部组织药物水平和低的全身递送，当沿沿着组织平面和在临床切除肉瘤手术中通常暴露的重要结构植入大型动物时。

 DESCRIPTION (provided by applicant): Local recurrence is the most common pattern of failure for retroperitoneal, abdominal, and pelvic (RAP) sarcomas. Despite a macroscopically complete resection, surgical margins are typically positive due to large tumor size and anatomic complexity, resulting in 5-year local recurrence rates of 50% to 90%. Mortality is due to locoregional rather than distant failure and therefore, strategies to improve survival must reduce locoregional failure rates. Trials evaluating perioperative and/or intraoperative external beam radiation therapy, single-dose hyperthermic intraperitoneal chemotherapy, and systemic chemotherapy have failed to demonstrate benefit. We recently developed a novel, flexible, tissue-conforming, biocompatible polymer film (Biomacromolecules, 2012, 13, 406-411) that can be placed intraoperatively over the entire tumor resection bed to slowly elute the chemotherapeutic drug paclitaxel ("Pax-films") locally and kill residual tumor cells. When utilized in our mouse surgical model of recurrent sarcoma, Pax-films markedly increased local tissue paclitaxel levels, avoided systemic toxicity, reduced locoregional recurrence rates, and improved overall survival without healing complications (Annals of Surgical Oncology, 2012, 19, 199-206.). Utilizing an organotypic in vitro culture method that preserves tumor architecture and microenvironment, enables pharmacodynamics profiling of a given tumor's response to chemotherapeutic drug delivery providing the means to predict which specific histologies, or potentially which specific patients, benefit the most from Pax-films. Lastly, we have established mouse xenograft models capable of rapid local tumor recurrence after surgery which allows us to evaluate efficacy of anti-neoplastic therapy against a variety of human sarcomas in vivo. With these skill sets and resources in hand, we can now address the following three specific aims: SPECIFIC AIM 1: Investigate efficacy and pharmacodynamic profiling of the Pax-film response against resected patient-derived sarcomas in vitro. SPECIFIC AIM 2: Define the pharmacodynamic profile and mechanism of action of Pax-films in the prevention of locoregional recurrence of human sarcoma xenografts in vivo. SPECIFIC AIM 3: Assess safety, feasibility, and perioperative morbidity of Pax-film implantation in a pre- clinical large animal model of surgical resection. Successful completion of this proposal will answer the hypothesis that prolonged exposure to paclitaxel-loaded polymer films will: 1) reduce tumor cell viability in vitro for human-derived sarcoma cell lines and patient tumor samples as assessed via organotypic culture; 2) reduce locoregional recurrence rates and improve survival in mouse surgical models of human sarcoma; and 3) prove to be safe and feasible for locoregional drug delivery, achieving high local tissue drug levels with low systemic delivery, when implanted in a large animal along tissue planes and vital structures commonly exposed during clinical extirpative sarcoma surgery.