Eradicating the single infiltration and tumor initiating population remains a difficult obstacle to achieve in Drain tumor therapy. The many functions of CD44 include modulating tyrosine kinase signaling leading to growth, interacting with cytoskeletal adaptor proteins to promote cell migration, and activating cell survival through drug transporters and anti-apoptotic proteins. These features make CD44 an ideal target to affect the diffusely infiltrative cancer stem cell population of residual brain tumors. My central hypothesis is that brain tumor stem cells utilize CD44 to promote invasion, self-renewal and tumor recurrence.
The aims of this proposal use a novel spontaneous mouse model of brain tumors developed in my lab to determine the affects of inhibiting CD44 facilitated signaling (Src, MAPK, and AKT) in glioma invasion and development. I will use CD44 knockout animals or inducible dominant negative mutants of CD44 for in vivo experiments using our highly flexible genetically engineered mouse model. In addition, I will utilize a variety of in vitro methods (Western blot, qPCR, ELISAs, and migration assays) to assess the effects of loss of function of CD44. The long-term goal of my PhD thesis is to better understand how CD44 function impacts glioma biology and use this information to instruct therapeutic development. As CD44 is expressed at minimal levels n the brain and overexpressed in tumor tissue, immunotherapy projects could be designed to eliminate cells overexpressing CD44. In addition, future work could use the expertise in my laboratory to design small molecules inhibitors and gene/antisense therapy regimes aimed at blocking CD44 cytoplasmic domain associations and/or CD44 binding to HA.
The long-term objective of my fellowship training is to understand brain tumor development, particularly with regard to CD44 biology. This information will be used to develop clinically feasible therapies for treating brain tumor patients.
| Klank, Rebecca L; Decker Grunke, Stacy A; Bangasser, Benjamin L et al. (2017) Biphasic Dependence of Glioma Survival and Cell Migration on CD44 Expression Level. Cell Rep 18:23-31 |
| Agarwal, Sagar; Mittapalli, Rajendar K; Zellmer, David M et al. (2012) Active efflux of Dasatinib from the brain limits efficacy against murine glioblastoma: broad implications for the clinical use of molecularly targeted agents. Mol Cancer Ther 11:2183-92 |
| Fujita, Mitsugu; Scheurer, Michael E; Decker, Stacy A et al. (2010) Role of type 1 IFNs in antiglioma immunosurveillance--using mouse studies to guide examination of novel prognostic markers in humans. Clin Cancer Res 16:3409-19 |
