Page 317 - 2014 Printable Abstract Book
P. 317
(PS5-52) Microenvironmental regulation of tumor growth, metastasis and response to combination
1
1
therapy via microenvironment-responsive nanochemotherpy and Radiation. Pallavi Sethi ; Amar Jyoti ;
3
1
1
2
4
Elden Swindell ; Ryan Chan ; Urlich W. Langner ; William H. St. Clair ; Ronald C. McGarry ; Thomas V.
1
2
1
O'Halloran ; Meenakshi Upreti , College of Pharmacy, University of Kentucky, Lexington, KY ; Chemistry
2
of Life Processes Institute, Northwestern University,, Evanston, IL ; Department of Radiation medicine,
3
University of Kentucky, Lexington, KY ; and Department of Radiation Medicine, University of Kentucky,
4
Lexington, KY
Several studies, including our own, have conclusively demonstrated that genetic alterations of
tumor cells are not the sole driving force behind tumor development. Instead, tumor growth, progression
and response to treatment are intimately controlled by the tumor microenvironment. Failing to account
for this cellular heterogeneity in tumors has impeded progress in treatment of cancer. We hope to
leverage the improved knowledge of cancer biology and our investigations of complex functional
interrelation between cellular and noncellular compartments of the tumor microenvironment to better
understand efficacy of combinatorial treatment strategies and direct evolution of novel cancer
nanotherapies. We have developed a novel 3D system to co-culture tumor cells and tumor associated
endothelial cells in vitro and then implant these spheroids in nude mice to better understand disease
progression, drug delivery and treatment response as it exists in vivo. We have demonstrated that tumor
endothelial spheroids better mimic the hypoxia and cell-cell interactions existing in solid tumors and that
radiation significantly enhances expression of Galectin-1 in tumor vasculature associated endothelial cells.
Galectin-1 is a specific receptor for the antiangiogenic peptide, Anginex and thus a promising candidate
for actively targeting irradiated tumors with anginex conjugated nanoparticles. Using our 3D model for
triple negative breast cancer, we have devised methods to study targeting of nanoparticles to this novel
radiation guided tumor microenvironment. Anginex conjugated nanoparticles carrying arsenic trioxide
and cisplatin are used to preferentially target irradiated tumor endothelial cells via radiation-induced
stromal enrichment of Galectin-1. Changes in fluorescence intensity of different cell types and spheroid
sizing is utilized as a method for high throughput therapeutic evaluation of combination therapy. Dorsal
skin fold window chamber spheroid implants facilitate imaging of neovascularization and response to
therapy in-vivo. This is the first study to understand a novel combinatorial nanotherapeutic system in an
in-vitro/ in-vivo tumor model incorporating stromal features and is expected to better predict treatment
response in patients. Support: NCI R21CA173609 & CNPP U01CA151461.
(PS5-53) An animal model to stimulate non-targeted response in radiotherapy patients. Hongning
Zhou; Kevin Hopkins; and Tom K. Hei, Columbia University, New York, NY
Radiation-induced bystander effect/non-targeted response has been well studied using various
biological endpoints, both in vitro and in vivo, in the past two decades. Development of brain tumors in
genetically susceptible mice as well as mutation induction in out of field lung tissues have recently been
reported in partially irradiated mice. Furthermore, there is clinical evidence that radiation induced
secondary tumors develop in out of field sites with exposure doses as little as 0.5Gy. These findings raise
an interesting research gap in knowledge: establishing a mouse model to mimic radiation therapy for
investigating the clinical relevance of radiation-induced non-targeted response. Prostate cancer is a
leading cause of illness and death among men in the western world. In addition, certain similarities
between the mouse and human prostate gland support the use of mouse models for elucidation of key
315 | P a g e
1
1
therapy via microenvironment-responsive nanochemotherpy and Radiation. Pallavi Sethi ; Amar Jyoti ;
3
1
1
2
4
Elden Swindell ; Ryan Chan ; Urlich W. Langner ; William H. St. Clair ; Ronald C. McGarry ; Thomas V.
1
2
1
O'Halloran ; Meenakshi Upreti , College of Pharmacy, University of Kentucky, Lexington, KY ; Chemistry
2
of Life Processes Institute, Northwestern University,, Evanston, IL ; Department of Radiation medicine,
3
University of Kentucky, Lexington, KY ; and Department of Radiation Medicine, University of Kentucky,
4
Lexington, KY
Several studies, including our own, have conclusively demonstrated that genetic alterations of
tumor cells are not the sole driving force behind tumor development. Instead, tumor growth, progression
and response to treatment are intimately controlled by the tumor microenvironment. Failing to account
for this cellular heterogeneity in tumors has impeded progress in treatment of cancer. We hope to
leverage the improved knowledge of cancer biology and our investigations of complex functional
interrelation between cellular and noncellular compartments of the tumor microenvironment to better
understand efficacy of combinatorial treatment strategies and direct evolution of novel cancer
nanotherapies. We have developed a novel 3D system to co-culture tumor cells and tumor associated
endothelial cells in vitro and then implant these spheroids in nude mice to better understand disease
progression, drug delivery and treatment response as it exists in vivo. We have demonstrated that tumor
endothelial spheroids better mimic the hypoxia and cell-cell interactions existing in solid tumors and that
radiation significantly enhances expression of Galectin-1 in tumor vasculature associated endothelial cells.
Galectin-1 is a specific receptor for the antiangiogenic peptide, Anginex and thus a promising candidate
for actively targeting irradiated tumors with anginex conjugated nanoparticles. Using our 3D model for
triple negative breast cancer, we have devised methods to study targeting of nanoparticles to this novel
radiation guided tumor microenvironment. Anginex conjugated nanoparticles carrying arsenic trioxide
and cisplatin are used to preferentially target irradiated tumor endothelial cells via radiation-induced
stromal enrichment of Galectin-1. Changes in fluorescence intensity of different cell types and spheroid
sizing is utilized as a method for high throughput therapeutic evaluation of combination therapy. Dorsal
skin fold window chamber spheroid implants facilitate imaging of neovascularization and response to
therapy in-vivo. This is the first study to understand a novel combinatorial nanotherapeutic system in an
in-vitro/ in-vivo tumor model incorporating stromal features and is expected to better predict treatment
response in patients. Support: NCI R21CA173609 & CNPP U01CA151461.
(PS5-53) An animal model to stimulate non-targeted response in radiotherapy patients. Hongning
Zhou; Kevin Hopkins; and Tom K. Hei, Columbia University, New York, NY
Radiation-induced bystander effect/non-targeted response has been well studied using various
biological endpoints, both in vitro and in vivo, in the past two decades. Development of brain tumors in
genetically susceptible mice as well as mutation induction in out of field lung tissues have recently been
reported in partially irradiated mice. Furthermore, there is clinical evidence that radiation induced
secondary tumors develop in out of field sites with exposure doses as little as 0.5Gy. These findings raise
an interesting research gap in knowledge: establishing a mouse model to mimic radiation therapy for
investigating the clinical relevance of radiation-induced non-targeted response. Prostate cancer is a
leading cause of illness and death among men in the western world. In addition, certain similarities
between the mouse and human prostate gland support the use of mouse models for elucidation of key
315 | P a g e
