Abstract
Abstract Several studies including our own have made it increasingly clear that genetic alterations of tumor cells alone are not the sole driving force behind tumor development but that tumor initiation, growth, progression and response to combinatorial treatments are rather intimately controlled by the microenvironment. Improved knowledge of cancer biology and investigation of the complex functional interrelation between the cellular and noncellular compartments of the tumor microenvironment have provided an ideal platform for the evolution of novel cancer nanotherapies. In the present study we have developed an in-vitro method to co-culture color coded triple negative breast carcinoma cells and cell types that exist in the tumor/tumor microenvironment in a “hanging drop” of medium to the size of an avascular microtissue (∼800 µm). Changes in the fluorescence intensity of different cell types and spheroid/microtissue sizing is being utilized as a method for high throughput therapeutic evaluation of the combination therapy using nanoparticles. When implanted orthotopically and in the dorsal skin fold window chambers in nude mice they facilitate the imaging of neovascularization and understanding response to therapy. We have also observed that radiation (3Gy) can significantly enhances expression of Galectin-1 in tumor vasculature associated endothelial cells which can serve as a specific ligand for the 33 amino acid antiangiogenic, anginex peptide. Thus Galectin-1 is a promising candidate for actively targeting irradiated tumors with anginex conjugated nanoparticles. The objective of this study is to establish a novel strategy for radiation therapy-amplified delivery of dual drugs for targeting the microenvironment-responsive endothelial component of the tumor vasculature. Use of radiation-guided anginex bound nanoparticles for delivery and controlled release of dual drugs (Arsenic-cisplatin) are expected to simulate metronomic therapy and preferentially target the tumor endothelial cells at the irradiated tumor site via tumor stroma enriched Galectin-1 protein. Our molecular studies indicate differential vulnerability for arsenic and cisplatin in cell types constituting the tumor/tumor microenvironment. This is the first study to understand a novel combinatorial nanotherapeutic system in an in-vitro/ in-vivo breast tumor model which incorporates characteristics of the tumor microenvironment and is thus expected to better predict treatment response in patients. Supported by NCI grant CA173609 and (CNPP) U01CA151461 Citation Format: Pallavi Sethi, Amar Jyoti, Elden Swindell, Ulrich W. Langner, William H. St. Clair, Ronald C. McGarry, Thomas V. O'Halloran, Meenakshi Upreti. Impact of tumor microenvironment on tumor growth, metastasis and response to combination therapy via microenvironment-responsive dual drug-loaded nanoparticles and radiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4589. doi:10.1158/1538-7445.AM2014-4589
Published Version
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