Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response.


Resistance of hypoxic solid tumor niches to chemotherapy and radiotherapy remains a major scientific challenge that calls for conceptually new approaches. Here we exploit a hitherto unrecognized ability of sickled erythrocytes (SSRBCs) but not normal RBCs (NLRBCs) to selectively target hypoxic tumor vascular microenviroment and induce diffuse vaso-occlusion. Within minutes after injection SSRBCs, but not NLRBCs, home and adhere to hypoxic 4T1 tumor vasculature with hemoglobin saturation levels at or below 10% that are distributed over 70% of the tumor space. The bound SSRBCs thereupon form microaggregates that obstruct/occlude up to 88% of tumor microvessels. Importantly, SSRBCs, but not normal RBCs, combined with exogenous prooxidant zinc protoporphyrin (ZnPP) induce a potent tumoricidal response via a mutual potentiating mechanism. In a clonogenic tumor cell survival assay, SSRBC surrogate hemin, along with H(2)O(2) and ZnPP demonstrate a similar mutual potentiation and tumoricidal effect. In contrast to existing treatments directed only to the hypoxic tumor cell, the present approach targets the hypoxic tumor vascular environment and induces injury to both tumor microvessels and tumor cells using intrinsic SSRBC-derived oxidants and locally generated ROS. Thus, the SSRBC appears to be a potent new tool for treatment of hypoxic solid tumors, which are notable for their resistance to existing cancer treatments.





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Publication Info

Terman, David S, Benjamin L Viglianti, Rahima Zennadi, Diane Fels, Richard J Boruta, Hong Yuan, Mathew R Dreher, Gerald Grant, et al. (2013). Sickle erythrocytes target cytotoxics to hypoxic tumor microvessels and potentiate a tumoricidal response. PLoS One, 8(1). p. e52543. 10.1371/journal.pone.0052543 Retrieved from

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Gerald Arthur Grant

Allan H. Friedman Distinguished Professor of Neurosurgery

Gregory M. Palmer

Professor of Radiation Oncology

Greg Palmer obtained his B.S. in Biomedical Engineering from Marquette University in 2000, after which he obtained his Ph.D. in BME from the University of Wisconsin, Madison. He is currently an Associate Professor in the Department of Radiation Oncology, Cancer Biology Division at Duke University Medical Center. His primary research focus has been identifying and exploiting the changes in absorption, scattering, and fluorescence properties of tissue associated with cancer progression and therapeutic response. To this end he has implemented a model-based approach for extracting absorber and scatterer properties from diffuse reflectance and fluorescence measurements. More recently he has developed quantitative imaging methodologies for intravital microscopy to characterize tumor functional and molecular response to radiation and chemotherapy. His awards have included the Jack Fowler Award from the Radiation Research Society.

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Marilyn Jo Telen

Wellcome Clinical Distinguished Professor of Medicine in Honor of R. Wayne Rundles, M.D.

Dr. Telen is recognized as an expert in the biochemistry and molecular genetics of blood group antigens and the pathophysiological mechanisms of vaso-occlusion in sickle cell disease. She is the Director of the Duke Comprehensive Sickle Cell Center.

Dr. Telen's laboratory focuses on structure/function analysis of membrane proteins expressed by erythroid cells, as well as the role of these proteins in non-erythroid cells. Proteins are also studied in transfectant systems, and research focuses especially on adhesion receptors. The goals of this work are (1) to understand the mechanism and role of red cell adhesion to leukocytes and endothelium in sickle cell disease; (2) to understand the signaling mechanisms leading to activation (and inactivation) of red cell adhesion molecules; (3) to understand the molecular basis of blood group antigen expression, and (4) to understand the interactions of erythroid membrane proteins with other cells and with extracellular matrix..

Recent investigations have focused on the role of signaling pathways in the upregulation of sickle red cell adhesion. Present studies include (1) investigation of beta-adrenergic signaling pathway responsible for activation of B-CAM/LU and LW adhesion receptors; (2) understanding how nitric oxide and ATP downregulate sickle red cell adhesion; (3) studying the effect of these processes in animal models.

Dr. Telen is also involved in a large multicenter study looking for genetic polymorphisms that affect clinical outcomes in sickle cell disease, as well as a multi-center study investigating the mechanisms and treatment of pulmonary hypertension in sickle cell disease.

Key Words:

Adhesion molecules
Erythrocyte membrane
Sickle cell disease
Transfusion medicine
Genetic polymorphisms


Mark Wesley Dewhirst

Gustavo S. Montana Distinguished Professor Emeritus of Radiation Oncology

Mark W. Dewhirst, DVM, PhD is the Gustavo S. Montana Professor of Radiation Oncology and Vice Director for Basic Science in the Duke Cancer Institute. Dr. Dewhirst has research interests in tumor hypoxia, angiogenesis, hyperthermia and drug transport. He has spent 30 years studying causes of tumor hypoxia and the use of hyperthermia to treat cancer. In collaboration with Professor David Needham in the Pratt School of Engineering, he has developed a novel thermally sensitive drug carrying liposome that has been successfully translated to human clinical trials. He has utilized the thermal characteristics of this liposome to develop an MR imageable form that can accurately reflect drug concentrations in tumors, which then is related to the extent of anti-tumor effect in pre-clinical models. This property has been widely used by other investigators, world-wide, particularly in the area of high intensity focused ultrasound, where it would be possible to literally paint drug to a target zone and visualize this process in real time, during heating. For his work in this area, Dr. Dewhirst was named a Fellow in the AAAS. Dr. Dewhirst has well over 500 peer-reviewed publications, book chapters and reviews, with >20,000 citations and an H-index of 73. He has given named lectures at the University of Western Ontario, Thomas Jefferson University and the New Zealand Cancer Society. He was awarded the Failla Medal and Lecture at the Radiation Research Society in 2008, the Eugene Robinson award for excellence hyperthermia research in 1992 and a similar award from the European Society for Hyperthermic Oncology in 2009. He was named a fellow of ASTRO in 2009 and was awarded the prestigious Gold Medal from the same society in 2012. He is a Senior Editor of Cancer Research and Editor-in-Chief of the International Journal of Hyperthermia. He has mentored 24 graduate students, and many postdoctoral fellows, residents, junior faculty and medical students. He has been particularly skillful in assisting those he has mentored to obtain DOD and NIH fellowships, K awards and first R01 grants. His skill in mentoring has been recognized by the Duke Comprehensive Cancer Center, the Medical Physics Graduate Training programs and the School of Medicine, where he has received “Mentor of the Year” awards. In 2011 he was selected to become the first Associate Dean of Faculty Mentoring in the Duke School of Medicine. In this position, he is implementing a comprehensive program to enhance success in obtaining NIH funding. He graduated from the University of Arizona in 1971 with a degree in Chemistry and Colorado State University in 1975 and 1979 with DVM and PhD degrees, respectively.

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