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.
New treatments are needed for retroperitoneal, abdominal, and pelvic (RAP) sarcomas, as the 5-year overall survival rates vary between 36% to 63% with local recurrence rates as high as 50% to 90%. Despite a macroscopically complete resection (the standard of care), margins are typically positive due to large tumor size and anatomic complexity. The current proposal evaluates a new, biocompatible, flexible polymeric device capable of local delivery of anti-neoplastic agents directly to the surgical bed in order to preven tumor recurrence and extend survival.
Mahvi, David A; Liu, Rong; Grinstaff, Mark W et al. (2018) Local Cancer Recurrence: The Realities, Challenges, and Opportunities for New Therapies. CA Cancer J Clin 68:488-505 |
Wang, Julia; Colson, Yolonda L; Grinstaff, Mark W (2018) Tension-Activated Delivery of Small Molecules and Proteins from Superhydrophobic Composites. Adv Healthc Mater 7:e1701096 |
Tevis, Kristie M; Colson, Yolonda L; Grinstaff, Mark W (2017) Embedded Spheroids as Models of the Cancer Microenvironment. Adv Biosyst 1: |
Digesu, Christopher S; Wiesel, Ory; Vaporciyan, Ara A et al. (2016) Management of Sarcoma Metastases to the Lung. Surg Oncol Clin N Am 25:721-33 |
Ricapito, Nicole G; Ghobril, Cynthia; Zhang, Heng et al. (2016) Synthetic Biomaterials from Metabolically Derived Synthons. Chem Rev 116:2664-704 |
Falde, Eric J; Yohe, Stefan T; Colson, Yolonda L et al. (2016) Superhydrophobic materials for biomedical applications. Biomaterials 104:87-103 |