Current Research Projects
Tumor-Associated Inflammation Mediated by Cytokines and Soluble Factors
Cell-cell interactions play a critical role during tumor progression. These events can be divided broadly into those resulting from direct cell-cell contact, or those resulting through diffusible factors. The overall goal of this project is to study the mechanism behind tumor-associated inflammation. High grade tumors are often infiltrated by macrophages and microglia. Dr. Gupta's group proposes that the accumulation of these cell types is mediated by specific cytokines, such as monocyte chemoattractant protein (MCP-1). Preliminary data demonstrates that tumor necrosis factor TNF-alpha strongly increases MCP-1 secretion, but this activity is reduced by inhibition of any of three major subgroups of the MAP kinase superfamily: extracellular signal-regulated kinases (ERK), p38 kinases, and the c-Jun NH2-terminal kinases (JNK). MCP-1 and its receptor, CCR2, are expressed by malignant glioma cells and may play a role in enhancing tumor-related migration. Future experiments will address the role of this cytokine and its cognate receptor using transgenic mouse models.
Convection-enhanced and Intranasal Delivery for the Treatment of Brainstem Glioma
Malignant brainstem gliomas occur primarily in children and are associated with a very poor prognosis. They are not amenable to surgical excision. Systemic chemotherapy often cannot result in adequate tissue concentrations to achieve tumor response. In collaboration with other BTRC labs, Dr. Gupta has developed an orthotopic brainstem tumor model that is being used to test new delivery strategies. These include direct positive pressure infusion of active drugs into the brainstem, and also by intra-nasal delivery. Preliminary data suggest that a wide variety of molecules are able to enter the CNS using these techniques and lead to a reduction in tumor growth. Further work will use liposomal packaged chemotherapeutic agents and inhibitory RNA molecules directed towards specific tumor targets.