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

新型植入式药物洗脱膜治疗肉瘤的功效和安全性

基本信息

批准号：
9206159
负责人：
Yolonda L Colson
金额：
$ 40.76万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-14 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9206159
关键词：
3-Dimensional Abdomen Address Adjuvant Therapy Anatomy Animal Model Animals Antineoplastic Agents Aorta Architecture Area Back Beds Bundling Cell Cycle Cell Cycle Kinetics Cell Death Cell Line Cell Survival Clinical Colon Data Development Devices Distant Dose Drug Delivery Systems Drug resistance Excision Exposure to External Beam Radiation Therapy Failure Film G1 Arrest G2/M Arrest Goals Hand Histology Human Image Implant In Vitro Incidence Inferior vena cava structure Invaded Left Left kidney Liver Medial Mediating Methods Microtubules Modeling Morbidity - disease rate Mus Nude Mice Operative Surgical Procedures Oranges Paclitaxel Pathway interactions Patients Pattern Pelvis Perioperative Pharmaceutical Preparations Pharmacodynamics Polymers Prevention Publications Recurrence Resected Residual Tumors Resources Retroperitoneal Space Right kidney Risk S-Phase Fraction Safety Sampling Site Solid Stromal Neoplasm Structure Surface Surgical Models Surgical Oncology Surgical margins Surgical sutures Survival Rate TP53 gene Time Tissue Harvesting Tissue imaging Tissues Tumor Tissue X-Ray Computed Tomography Xenograft Model Xenograft procedure biocompatible polymer biomacromolecule biomaterial compatibility cancer cell chemotherapy clinical practice flexibility healing implantation improved in vivo intraperitoneal therapy killings mortality neoplastic cell novel novel strategies pre-clinical prevent profiles in patients programs public health relevance reconstruction research clinical testing response safety and feasibility sarcoma skills soft tissue standard of care systemic toxicity tumor tumor microenvironment

项目摘要

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.