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。尽管大体完全切除，但由于肿瘤体积大和解剖复杂，手术切缘通常是阳性的，导致5年内局部复发率为50%至90%。死亡率是由于局部失败率，而不是远距离失败率，因此，提高存活率的策略必须降低局部失败率。评估围手术期和/或术中外照射治疗、单剂热疗腹膜内化疗和全身化疗的试验均未显示出益处。我们最近开发了一种新型的、灵活的、与组织相适应的、生物相容的聚合物膜(Biomacromoles，2012，13,406-411)，可以在术中放置在整个肿瘤切除床上，以缓慢地在局部洗脱化疗药物紫杉醇(简称Pax膜)，并杀死残留的肿瘤细胞。当被利用时 在我们的复发肉瘤的小鼠外科模型中，Pax膜显著增加了局部组织紫杉醇的水平，避免了全身毒性，降低了局部复发率，并提高了总体存活率，而没有愈合并发症(Annals of Surgical Oncology，2012，19,199-206.)。利用保存肿瘤结构和微环境的有机体外培养方法，能够对特定肿瘤对化疗药物的反应进行药效学分析，从而提供预测哪些特定组织或潜在的特定患者从Pax-Filters中受益最大的手段。最后，我们建立了能够在手术后快速局部复发的小鼠异种移植模型，这使得我们能够在体内评估抗肿瘤治疗对各种人类肉瘤的疗效。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：特定目标1：研究Pax膜在体外对切除患者来源的肉瘤的疗效和药效学特征。特定目的2：明确Pax膜在体内预防人肉瘤移植瘤局部区域复发的药效学特征和作用机制。具体目的3：在临床前的大动物手术切除模型中评估Pax膜植入的安全性、可行性和围手术期发病率。这项提议的成功完成将回答这样的假设，即长期接触紫杉醇聚合物薄膜将：1)降低体外肿瘤细胞的活力 对于通过器官型培养评估的人源性肉瘤细胞系和患者肿瘤样本，该药物被证明是安全和可行的；2)在人类肉瘤的小鼠外科模型中，可降低局部复发率并提高存活率；3)局部给药被证明是安全可行的，当沿着临床根除肉瘤手术中经常暴露的组织平面和重要结构植入大型动物体内时，可实现高局部组织药物浓度和低系统给药。

 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.