Health Research, Inc.
Grant: $208,350 - National Institutes of Health - Apr. 28, 2009
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Award Description: The aim of this funded R21 proposal is to study the role of dietary supplement selenium (Methylselenocysteine or MSC) in supranutritional doses in retarding cancer growth and synergistically enhancing chemotherapeutic efficacy in combination setting through its? antiangiogenic activity. This antiangiogenic effect lead to tumor blood vessel normalization that enabled delivery of higher drug within the tumor at a given systemic drug dose administered. This effect was hypothesized to be through down regulation of reactive oxygen species leading to HIF-1á degradation. The proposal uses six different human cancer xenografts from three cancer disease sites ? Head and Neck, Colorectal and Lung. The specific aims of the proposal are as under: Specific Aim 1: Evaluate the effect of Se on antioxidant and vascular (antiangiogenic and normalization) status in tumor xenografts growing sub cutaneously (s.c) in nude mice. Specific Aim 2: Evaluate the effect of Se on tumor vascular volume and permeability using noninvasive dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Specific Aim 3: Evaluate the effect of Se in vitro on ROS, antioxidants, HIF-1á degradation and on downstream angiogenic markers VEGF, PDGF-B, and MMP-14.
Project Description: Aim 1: Findings reported (Clin. Colo. Can., vol 8(3), 155, 2009): a. Tumor inhibition by MSC in FaDu, HCT-8 and HT-29 was found to be associated with a lower tumor microvessel density (MVD), a higher vascular normalization and a lower tumor interstitial fluid pressure in FaDu, HCT-8 but not in HT-29 - a more resistant phenotype. B. MSC (0.2 mg/mice/day p.o. x 14) led to a higher doxorubicin delivery in FaDu, HCT-8 and HT-29 xenografts. C. Tumor morphologic heterogeneity is a direct determinant of the magnitude of synergistic efficacy seen. Currently other studies are ongoing. Aim 2: Result of FaDu, HCT-8 and HT-29 xenografts has been published and parallels the normalization observation seen in aim 1 above. Studies with the lung xenografts and human head and neck surgical cancer samples are ongoing. Aim 3: HIF-1á down regulation by Se has been confirmed in FaDu and A253 xenografts. Proposed studies on reactive oxygen species/antioxidant levels have been initiated. Se-induced inhibition of HIF-1á in vitro was found to be concentration and time dependent with inhibition seen at 16-18 h and complete degradation seen at 24 h at a dose of 0.8 ? 1.0 µM of Se in FaDu cells. In contrast, the relatively resistant head and neck tumor counterpart, A253 cells required higher concentration of Se (~2 µM) for a similar maximum HIF-1á inhibitory effect. HIF-1á driven luciferase reporter construct has been initiated with generation of stably transfected tumor cells that are underway. Using HIF-1á siRNA this inhibitory effect was confirmed in vitro in FaDu cells. Stable shRNA HIF-1á Knockdown FaDu cells were found to grow at a slower rate in vivo. MSC treatment did not further enhance the growth inhibitory effects seen with the knockdown FaDu cells in vivo. Further, HIF-1á inhibition through shRNA was found to down regulate vascular endothelial growth factor (VEGF) while studies with other HIF-1á transactivated genes such as MMP-14 and PDGF-B is underway.
Jobs Summary: The following job titles and job descriptions performed activities on this ARRA funded project . The mission of Roswell Park is to understand, prevent and cure cancer. The ARRA funding provided is to help realize this mission. Affiliate Member: Conducts original clinical research and adds to the base of scientific knowledge; participates in all phases of the research process; may teach in graduate education programs; and may generate peer-reviewed funding for Institute clinical research projects. Research Associate: Performs a variety of routine and specialized laboratory tests and experimental procedures for the purpose of original research which generally are within a well-defined body of scientific knowledge and typically contribute to larger research efforts of independent investigators. Lab technician: Performs technical laboratory work of advanced difficulty in a scientific research laboratory; utilizes quantitative and qualitative techniques to analyze laboratory samples; prepares standard media, cultures, reagents, stains and solutions; participates in and performs assigned phases of scientific research projects; operates and cares for laboratory equipment; maintains laboratory supplies and related inventory. PBC Scientist: Performs basic and applied research involving the formulation, conduct, analysis, interpretation and reporting of scientific investigations of phenomena or problems associated with the cause, cure, treatment, and prevention of cancer; conducts and may supervise phases of creative, original and independent scientific research studies in a specific field of assignment; defines problems and issues that enhances the development of scientific research programs; contributes significantly to a base of scientific knowledge; may teach in graduate education programs; generates peer-reviewed funding for Institute scientific research projects. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
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